The subcortical auditory structures in the Mongolian gerbil: II. Frequency-related topography of the connections with cortical field AI

The Subcortical Auditory Structures in the MongolianGerbil: II. Frequency-Related Topography of theConnections with Cortical Field AI

Eike Budinger,1,3,4* Michael Brosch,2,3 Henning Scheich,1,3 and Judith Mylius2

1Department of Auditory Learning and Speech, Leibniz Institute for Neurobiology, D-39118 Magdeburg, Germany2Special Laboratory for Primate Neurobiology, Leibniz Institute for Neurobiology, D-39118 Magdeburg, Germany3Center for Behavioral Brain Sciences, Universit€atsplatz 2, G24-005, D-39106 Magdeburg, Germany4Clinic of Neurology II, Otto-von-Guericke-University Magdeburg, D-39120 Magdeburg, Germany

ABSTRACTWe investigated the frequency-related topography of

connections of the primary auditory cortical field (AI) in

the Mongolian gerbil with subcortical structures of the

auditory system by means of the axonal transport of

two bidirectional tracers, which were simultaneously

injected into regions of AI with different best frequen-

cies (BFs). We found topographic, most likely fre-

quency-matched (tonotopic) connections as well as

non-topographic (non-tonotopic) connections. AI proj-

ects in a tonotopic way to the ipsilateral ventral (MGv)

and dorsal divisions (MGd) of the medial geniculate

body (MGB), the reticular thalamic nucleus and dorsal

nucleus of the lateral lemniscus, and the ipsi- and con-

tralateral dorsal cortex of the inferior colliculus (IC) and

central nucleus of the IC. AI receives tonotopic inputs

from MGv and MGd. Projections from different BF

regions of AI terminate in a non-tonotopic way in the ip-

silateral medial division of the MGB (MGm), the supra-

geniculate thalamic nucleus (SG) and brachium of the

IC (bic), and the ipsi- and contralateral external cortex

and pericollicular areas of the IC. The anterograde

labeling in the intermediate and ventral nucleus of the

lateral lemniscus, parts of the superior olivary complex,

and divisions of the cochlear nucleus was generally

sparse; thus a clear topographic arrangement of the la-

beled axons could not be ruled out. AI receives non-

tonotopic inputs from the ipsilateral MGm, SG, and bic.

In conclusion, the tonotopic and non-tonotopic cortico-

fugal connections of AI can potentially serve for both

conservation and integration of frequency-specific infor-

mation in the respective target structures. J. Comp.

Neurol. 521:2772–2797, 2013.

VC 2013 Wiley Periodicals, Inc.

INDEXING TERMS: anterograde; brainstem; confocal laser scanning microscopy; dextran amine; primary auditory cortex;

retrograde; rodent

One of the most important characteristics of acoustic

stimuli is their spectral composition (Eggermont, 2001).

Spectral information is conveyed along the entire auditory

pathway and is represented in the tonotopic (cochleo-

topic) maps at all functional–anatomical levels from the

cochlea up to the auditory cortex (for review, see Rouiller,

1997; Malmierca and Merchan, 2004). Within the tono-

topically organized lemniscal (core) part of the ascending

auditory pathway, frequency-specific information is for-

warded via essentially parallel point-to-point connections

between neurons having similar best frequencies (BFs)

(Andersen et al., 1980a; Calford and Aitkin, 1983; Brand-

ner and Redies, 1990; Hu, 2003; Velenovsky et al., 2003;

Hackett et al., 2011). In contrast, within its non-lemniscal

part, such a tonotopic organization is not evident, and

connections appear rather diffuse (Rouiller, 1997; Mal-

mierca and Merchan, 2004).

Both tonotopic and non-tonotopic connections might

also be present in the descending auditory pathway.

Once assumed to be organized as a chain of descending

projections mainly between adjacent subcortical auditory

Additional Supporting Information may be found in the online version ofthis article.

Grant sponsor: State Sachsen-Anhalt; Bundesministerium fur Bildungund Forschung (BMBF); Deutsche Forschungsgesellschaft (DFG); Grantnumber: SFB TR 31.

*CORRESPONDENCE TO: Eike Budinger, Ph.D., Department of AuditoryLearning and Speech, Leibniz Institute for Neurobiology, Brenneckestr. 6,D-39118 Magdeburg, Germany. E-mail: [email protected]

VC 2013 Wiley Periodicals, Inc.

Received September 28, 2012; Revised December 20, 2012; AcceptedJanuary 23, 2013

DOI 10.1002/cne.23314

Published online February 14, 2013 in Wiley Online Library(wileyonlinelibrary.com)

2772 The Journal of Comparative Neurology | Research in Systems Neuroscience 521:2772–2797 (2013)

RESEARCH ARTICLE

levels (for review, see Spangler and Warr, 1991), the de-

scending pathways are now known to include long-range

connections bypassing several of these levels (for review,

see Malmierca and Merchan, 2004). Even the auditory

cortex projects directly to virtually all subcortical auditory

nuclei (for review, see Winer, 2006; Nunez and Malmierca,

2007). Although it is largely unknown how the corticofugal

connections modulate the activity of neurons in the target

structures under natural conditions (Bajo et al., 2010),

there is an increasing number of studies demonstrating a

powerful corticofugal control of the ascending auditory

pathway under experimental situations.

For example, it was shown that the electric stimulation

of neurons with a given BF in the primary auditory cortex

leads to an increase of the responses (facilitation), a

shortening of response latencies, and a sharpening of fre-

quency tuning curves of physiologically matched neurons

(same BF) in the auditory thalamus (Watanabe et al.,

1966; He, 1997; Zhang and Suga, 2000; He et al., 2002;

Yu et al., 2004; Tang et al., 2012), inferior colliculus (Syka

and Popelar, 1984; Yan and Suga, 1998; Zhang and Suga,

2000; Jen et al., 2002; Yan and Ehret, 2002; Yan et al.,

2005), and even cochlear nucleus (Jacomme et al., 2003;

Luo et al., 2008; Liu et al., 2010). In contrast, non-

matched neurons (different BF) often showed a decrease

of the responsiveness (inhibition), a lengthening of

response latencies, and a shift of frequency tuning curves

toward (centripetal) or away (centrifugal) from those of

the activated neurons in auditory cortex. Likewise, a

selective cortical inactivation reduces the activity of fre-

quency-matched subcortical neurons and elevates the ac-

tivity of non-matched neurons together with a shift of

their BF toward that of the inactivated cortical neurons

(Ryugo and Weinberger, 1976; Villa et al., 1991; Zhang

and Suga, 1997; Nakamoto et al., 2008, 2010; Antunes

and Malmierca, 2011; Bauerle et al., 2011).

The anatomical substrate underlying these and other

cortically induced plastic changes in subcortical auditory

activity may involve a variety of different, but not mutually

exclusive neuronal networks. Among these, tonotopic

and non-tonotopic corticofugal projections, which termi-

nate directly (or indirectly via local inhibitory interneur-

ons) on the ascending auditory neurons, certainly play a

fundamental role (for review and discussion, see Saldana

et al., 1996; Jen et al., 2002; He, 2003a; Suga and Ma,

2003; Yan et al., 2005; Lim and Anderson, 2007; Mal-

mierca and Ryugo, 2011; Suga, 2012). Nevertheless, still

not much is known about the organization of these corti-

cofugal connections and in particular about their relation-

ship to the tonotopic or other functional maps of their

cortical origins and subcortical targets. In order to

approach this issue, we investigated the frequency-

related topography of the direct connections between the

Abbreviations

Auditory cortex

AI primary auditoryfield

AAF anterior audi-tory field

AV anteroventralauditoryfield

D dorsal auditoryfield

DP dorsoposteriorauditoryfield

V ventral auditoryfield

VM ventromedialauditoryfield

VP ventroposteriorauditoryfield

Brain structures

8n vestibuloco-chlear nerve

anr auditory nerveroot

ar acousticradiation

AVCN anteroventralcochlearnucleus

bic brachium of theIC

bsc brachium of theSC

Cb cerebellumcic commissure of

the ICCIC central nucleus

of the ICCN cochlear nucleiCp cerebral

peduncleCu cuneiform

nucleusDCIC dorsal cortex of

the ICDCN dorsal cochlear

nucleusDD deep dorsal

nucleus ofthe MGd

DLG dorsal lateralgeniculatenucleus

DM dorsomedial nu-cleus of theIC

DNLL dorsal nucleusof thelaterallemniscus

DR dorsal raphenucleus

ECIC external cortexof the IC

eml external medul-lary lamina

gca globular cellarea

IC inferiorcolliculus

ic internal capsuleicv inferior cerebral

veinINLL intermediate

nucleus ofthe laterallemniscus

LNTB lateral nucleusof thetrapezoidbody

LP lateral posteriorthalamicnucleus

LSO lateral superiorolive

Lv MGv, parslateralis

mca middle cerebralartery

MGB medial genicu-late body

MGd/m/v medial genicu-late body,dorsal/medial/ven-tral division

MNTB medial nucleusof thetrapezoidbody

MSO medial superiorolive

MZMG marginal zoneof the MGB

NLL nuclei of thelaterallemniscus

OB olfactory bulbopt optic tractoca octopus cell

areaOv MGv, pars

ovoideaPo(T) posterior tha-

lamic nu-clear group(triangular)

Pta pericolliculartegmentalarea

PTN paracentral tec-tal nuclei

PVCN posteroventralcochlearnucleus

py pyramidal tractrp rostral pole of

the MGvRt reticular tha-

lamicnucleus

Sag sagulumnucleus

SC superiorcolliculus

sca spherical cellarea

SG suprageniculatenucleus

sgcl superficial gran-ule celllayer

SN substantia nigraSOC superior olivary

complexSPN superior perioli-

vary nucleusstr superior tha-

lamicradiation

tb (fibers of the)trapezoid

The auditory corticofugal system of the gerbil

The Journal of Comparative Neurology | Research in Systems Neuroscience 2773

primary auditory cortical field (AI) and the subcortical au-

ditory structures in the Mongolian gerbil (Meriones ungui-

culatus), a frequently used animal model in auditory

research (Budinger and Klump, 2008; Budinger and

Scheich, 2009).

MATERIALS AND METHODS

Twenty-two young adult male Mongolian gerbils (Mer-

iones unguiculatus), 4–6 months old and weighing 70–

100 g, were used for this study. All experiments were

approved by the animal care committee of the State

Sachsen-Anhalt, Germany (no. 43.2-42502/2-2-325 IFN

MD) and are in accordance with the Guide for the Care

and Use of Laboratory Animals (NIH, 2011).

Tracing experimentsThe experimental procedures used for the neuronal

tract tracing in the present study, are largely similar to

those described in previous reports (Budinger et al.,

2006, 2008).

Fourteen gerbils were anesthetized with ketamine (10

mg/100 g body weight, ip) and xylazine (0.5 mg/100 g

body weight, ip), and a craniotomy was performed to ex-

pose the left auditory cortex. A closeable custom-made

plastic chamber was mounted around this opening with

dental acrylic. For subsequent head fixation, a small alu-

minum bar was installed on the frontal skull. Prior to the

tracer injections (see below), we first mapped parts of

the auditory cortex by recording electrophysiological sig-

nals (single- and multi-unit activity) or by optical recording

of intrinsic signals (ORIS). These recordings were per-

formed in order to identify the location, borders, and

extent of the AI, to establish reliable coordinates of the AI

with respect to landmarks on the skull (e.g., lambda) and

on the cortical surface (e.g., characteristic blood vessels)

and to picture the tonotopic organization of the AI.

For the electrophysiological recordings we used a lin-

ear array of seven fiber microelectrodes, which had an

inter-electrode separation of 300 lm and in which the

electrodes could be moved independently from each

other (Thomas Recording, Giessen, Germany). BFs were

evaluated while we stimulated the gerbils acoustically

with pure tones of 100-ms (repetition rate 2 Hz) or 200-

ms duration (repetition rate 1 Hz) presented over a vari-

able range of frequencies, which was selected according

to the estimated frequency selectivity of the recorded

neurons (Brosch et al., 1999). Tones were presented at

70 dB sound pressure level (SPL) under free-field condi-

tions. The tone that elicited the greatest number of spikes

during the tone presentation was termed BF. After the

brief microelectrode mapping of the AI, two to four elec-

trodes were replaced by moveable fine glass fiber pip-

ettes (tip diameter 20 lm; Thomas Recording, Germany),

which were connected to an oil hydraulic syringe system

(Hamilton Europe, Bonzduz, Switzerland). These pipettes

were used to apply the two different tracers at two differ-

ent BF locations of the AI during the next recording ses-

sion (Fig. 1B, Table 1; see also below).

For ORIS, which measures light absorbance changes at

a wavelength of 605 nm consequent upon activity-de-

pendent changes in deoxyhemoglobin (Hess et al., 2000),

animals were stimulated with pure tones (0.25, 1, 2, 4, 8,

and 12 kHz) of 200-ms duration. These were presented at

a rate of 2.5 Hz and at 70 dB SPL (for further details, see

Budinger et al., 2006). After imaging the auditory cortex,

two different tracers (see below) were slowly injected at

two different BF locations of the AI (Table 1) by using very

fine glass pipettes (tip diameter 20 lm) and an oil hydrau-

lic nanoliter injection system (WPI, Berlin, Germany). The

latter was mounted on the stereotaxic apparatus of the

setup (David Kopf Instruments, Tujunga, CA).

In five cases without prior electrophysiological or opti-

cal recordings, we relied on previously established ste-

reotaxic coordinates of the AI relative to landmarks on

the skull, such as lambda, and to conspicuous features of

the cortical vasculature, such as characteristic branches

of the inferior cerebral vein (icv) and the middle cerebral

artery (mca; Budinger et al., 2000a, 2006, 2008; Fig. 1A).

Stereotaxic injections were performed as described for

ORIS.

In each gerbil, 70 nl of 10% fluorescein-labeled dextran

(FD) and 70 nl of 10% tetramethylrhodamine-labeled dex-

tran (TMRD) (both of 10,000 MW, lysine-fixable; Molecu-

lar Probes, Eugene, OR; dissolved in Aqua dest. contain-

ing 0.1% sodium azide and 1% dimethyl sulfoxide) were

injected immediately after each other into two different

BF representations of the AI. The possibility of a tracer

spread into the fields adjacent to the AI was excluded

because 1) in the experimental cases involving electro-

physiological and ORIS recordings, the borders of the AI

were briefly mapped and the injections were performed

at least 0.3 mm inside the border; 2) in the experimental

bodyVLG ventral lateral

geniculatenucleus

VNLL ventral nucleusof thelaterallemniscus

VNTB ventral nucleusof thetrapezoidbody

VPL ventral poste-rior lateralthalamicnucleus

Others

BF best frequency

c caudald dorsalFD fluorescein-la-

beleddextran

hf high frequencyl laterallf low frequencym medialr rostralORIS optical record-

ing ofintrinsicsignals

TMRD tetramethylr-hodamine-la-beleddextran

v Ventral

Budinger et al.

2774 The Journal of Comparative Neurology |Research in Systems Neuroscience

Figure 1. A: Lateral view of the brain of a Mongolian gerbil with superimposed outlines of the auditory cortex, which consists of the primary (AI), an-

terior (AAF), dorsal (D), dorsoposterior (DP), ventroposterior (VP), ventral (V), ventromedial (VM), and anteroventral field (AV) (modified from Budinger

and Scheich, 2009). AI is located between well-distinguishable branches of the inferior cerebral vein (icv; black arrows and arrowhead) and the middle

cerebral artery (mca; white arrow and arrowhead). The approximate locations of the tracer injection sites into high-frequency (hf) and low-frequency (lf)

regions of AI, respectively, are indicated by the tips of the green and red pipette. The injections were guided by prior recordings of electrophysiological

or intrinsic optical signals or by stereotaxic information (for further information, see Table 1). The spatial distribution of best frequencies (BFs) is illus-

trated by the map on the right-hand side. For other abbreviations, see list. B: Sagittal section through a gerbil’s left hemisphere (animal G148). The

injections of fluorescein-labeled dextran (FD; green fluorescent) and tetramethylrhodamine-labeled dextran (TMRD; red fluorescent) were placed into

two different BF locations of AI. Stars indicate the positions of three recording metal electrodes (nos. 6, 5, 3) and the two glass injection pipettes

(nos. 7, 4), of which no. 7 was used for the FD injection into the rostral hf location (BF � 20.0 kHz) and no. 4 for the TMRD injection into the caudal

lf location of AI (BF � 1.5 kHz). BFs at the recording sites (15.7, 1.9, and 1.1 kHz) were obtained from the neuronal responses to tones of different

frequencies (lower panels). BFs at the injection sites were estimated from recordings at these locations, from BFs at neighboring recording sites, and

from the average spatial BF gradient of AI. Stimuli were pure tones of 100-ms duration, denoted by the white bars above the time axes. Frequency

was varied, as indicated on the ordinate. Spike rates are color-coded: dark blue codes the average (spontaneous) activity during the intertone intervals;

spike rates that are significantly above this rate are plotted with warmer colors. (A magenta–green version of this figure has been posted as a supple-

mentary file for the assistance of color-blind readers.) Scale bar ¼ 2 mm in A; 0.5 mm in B.

cases using stereotaxic coordinates and landmarks, the

injections were also placed far enough from the esti-

mated field borders; more specifically, injections were

always performed caudal to a distinct ascending branch

of the icv and rostral to a distinct descending branch of

the mca (Fig. 1); and (3) injection sites had a maximum di-

ameter of 300 lm, i.e., a maximum radius of 150 lm (Ta-

ble 1). Due to the above-mentioned conventions, our

injections were always more than 150 lm away from the

field borders and thus were always limited to the AI. The

possibility of a tracer uptake by (damaged) fibers of pas-

sage was minimized by slowly injecting small amounts

(5X 14-nl injection steps over 5 minutes) of the low con-

centrated (10%) tracers solutions by using very fine glass

pipettes (tip diameter 20 lm) (see also Nance and Burns,

1990; Rajakumar et al., 1993).

After the injections, the recording chamber was closed

by an appropriate lid or the surgical opening was closed

with bone wax (Ethicon, Johnson & Johnson, Warren, NJ)

and a tissue adhesive (Histoacryl, Braun, Melsungen, Ger-

many). Thereafter, animals were allowed to recover.

Seven days after the tracer injections, gerbils were

reanesthetized (20 mg ketamine and 1.0 mg xylazine per

100 g body weight, ip) and perfused transcardially with

50 ml of 0.1 M phosphate-buffered saline (PBS; pH 7.4),

followed by 200 ml of 4% paraformaldehyde in PBS. The

brains were removed and postfixed overnight in 4% para-

formaldehyde and then cryoprotected in 30% sucrose in

PBS for 48 hours at 4�C. Then they were cut on a freezing

microtome into 50-lm-thick horizontal (five brains), fron-

tal (four brains), or sagittal sections (five brains; Table 1),

which were collected in 0.1 M PBS. Every fourth section

was counterstained for cell bodies with a fluorescent

Nissl stain (NeuroTrace, Molecular Probes; 1:100 in PBS).

Finally, all sections were mounted on gelatin-coated

slides and coverslipped with 50% glycerin in PBS contain-

ing 0.1% diazabicyclo(2.2.2.)octane.

Golgi experimentsFor the depiction of the cyto- and fibroarchitecture of

the gerbil’s subcortical auditory structures by means of

the Golgi–Cox technique (Glaser and Van der Loos,

1981), we used the same histological specimens as

described in detail in our companion paper (Mylius et al.,

2012).

Data analysisAll preparations were examined by means of a com-

bined light and fluorescence microscope system (Leica,

Nussloch, Germany). For analysis of the FD and TMRD

transport, the appropriate optical filter sets (Leica) were

used. FD has an excitation maximum of 494 nm and an

emission maximum of 518 nm (green fluorescent), TMRD

of 555 nm and 580 nm (red fluorescent), and NeuroTrace

of 435 nm and 455 nm (blue fluorescent), respectively.

Double- (FD- and TMRD-) labeled neuronal elements were

identified by their yellow fluorescence.

Tonotopic corticofugal projections of the AI were

defined by topographically disjunct, single-labeled axons

TABLE 1.

Experimental Animals1

Case Sectioning

Diameter

FD (lm)

Layers

FD

BF FD

(kHz)

Diameter

TMRD (lm)

Layers

TMRD

BF TMRD

(kHz)

Distance

between injection

sites (lm)

BF

evaluation

G 145 Frontal 280 IV–Vb �0.5 259 IV–VI �3 726 stereoG 146 Horizontal 244 III–Va 2.0 270 IV–VI 0.5 600 e-physG 147 Horizontal 223 III–Va 1.0 238 III–Va 12.0 728 ORISG 148 Sagittal 280 II/III–Va 20.0 263 III/IV–Vb 1.5 900 e-physG 149 Frontal 279 II/III–Va �10 220 IV–Vb �0.5 1,100 stereoG 150 Horizontal 225 III–Va �16 252 II/III–Va �1 817 stereoG 155 Horizontal 228 II–IV 0.25 247 II–IV 1.0 802 ORISG 156 Horizontal 276 II/III–Va 4.0 225 II–IV 1.0 603 ORISG 162 Sagittal 218 III–Va 12.0 265 III–Va 1.0 806 ORISG 164 Sagittal 226 III–Va 2.0 244 III–Va 0.25 950 ORISG 190 Frontal 267 IV–Vb �1 240 III–Va �0.25 715 stereoG 191 Frontal 278 IV–Vb 0.25 253 IV–VI 1.0 797 ORISG 213 Sagittal 288 III/IV–Vb 8.0 292 III/IV–Vb 1.0 707 ORISG 214 Sagittal 301 III/IV–Vb �1 295 III/IV–Vb �32 986 stereoMean 6 SD 258.1 6 29.1 254.5 6 21.9 802.6 6 142.1

1Case number, plane of brain sections, and diameter of, layers covered by, and distances between injection sites of fluorescein-labeled (FD) and

tetramethylrhodamine-labeled dextran (TMRD) into AI of the gerbil as well as the best frequency (BF) of neurons at the injection sites, listed for

each of the 14 experimental animals. The BFs were either established by using recordings of electrophysiological signals (e-phys), of optical intrin-

sic signals (ORIS) or by using stereotaxic information (stereo). Means 6 1 standard deviation (SD) of the diameters of and of the distances

between the injection sites are given in the last line.

Budinger et al.


and their terminations in the respective target structures.

Non-tonotopic projections were identified by diffuse and

spatially overlapping (convergent) single-labeled axons in

the target areas. For the retrograde tracer transport,

tonotopic inputs into the AI were defined by topographi-

cally disjunct, single-labeled somata in the brain struc-

tures of origin. Non-tonotopic inputs were determined by

diffusely distributed single-labeled somata as well as by

double-labeled cell bodies of origin (the latter in particular

identifying divergent inputs into the AI). In addition, the

degree of spatial overlap of the retrograde and antero-

grade labeling provided information about the degree of

reciprocity of the respective connections.

The diameters of the injection sites, which consisted of

the actual tracer application site (focus) and a small zone

of densely stained but indistinguishable neuronal ele-

ments (halo), were measured directly in the sections by

using a micrometer calibration grid mounted within the

lens tube of the microscope. If the injection sites covered

several sections, an appropriate mean of the diameter

was calculated. Similarly, the distances between FD and

TMRD injection foci were measured directly in horizontal

and sagittal sections. In frontal sections, the numbers of

sections between the foci of the two injection sites were

counted and multiplied by the section thickness of 50

lm. The diameters and distances, which are all listed in

Table 1, include a 10% correction for tissue shrinkage.

As described above, BFs were ideally established elec-

trophysiologically or with ORIS (Table 1). In cases of ste-

reotaxic injections, BFs were estimated post hoc in partic-

ular by the locations of the injection sites relative to

internal landmarks, such as the hippocampus and the audi-

tory koniocortex (for details, see Budinger et al., 2000a,

2008). For example, at the dorsoventral level of the AI, the

rostral pole of the hippocampal formation lies at the same

rostrocaudal position as the 1-kHz isofrequency contour in

the AI (Scheich et al., 1993). Injection sites were therefore

considered as located in BF areas >1 kHz, �1 kHz, or <1

kHz, when they were located rostral, close, or caudal to

this hippocampal reference, respectively. Furthermore, we

considered the fact that the spatial resolution for tonotopic

mapping of frequencies within the AI is about 200 lm per

octave for frequencies > 1 kHz and about 400 lm per

octave for frequencies < 1 kHz (Scheich et al., 1993). The

BFs at the locations of stereotaxic injections were conse-

quently estimated according to this information (Table 1)

by measuring the distance between the hippocampal refer-

ence and the injection sites.

The assignment of the FD- and TMRD-labeled subcorti-

cal auditory structures was based on:

1. Previous studies on the cyto-, fibro-, and chemoarchi-

tecture of the gerbil’s auditory pathway (e.g., cochlear

nuclear complex: Gleich, 1994; Cant and Benson,

2006b; superior olivary complex: Helfert and Schwartz,

1987; Sanes et al., 1990, 1992; Braun and Piepen-

stock, 1993; nuclei of the lateral lemniscus: Nordeen

et al., 1983; Benson and Cant, 2008; inferior colliculi:

Bajo and Moore, 2005; Cant and Benson, 2005,

2006a; medial geniculate body: Budinger et al., 2000b;

Cant and Benson, 2007; auditory cortex: Budinger

et al., 2000a), and brain (Loskota et al., 1974; Thies-

sen and Yahr, 1977; Gonzalez-Lima and Jones, 1994)

2. The Golgi preparations, which were presented here

and in our companion paper (Mylius et al., 2012), and

3. Stereotaxic atlases and descriptions of the mouse

(Dong, 2008; Franklin and Paxinos, 2008; Watson

and Paxinos, 2010) and rat (Paxinos, 1995; Paxinos,

2004; Paxinos et al., 1999a,b; Swanson, 2004; Paxi-

nos and Watson, 2007).

Regions of interest containing the fluorescent tracer

labeling were usually too large and too finely stained for

single-shot photography in one focal plane. Thus, they

were scanned in at least two focal planes and in mean-

ders (Zuschratter et al., 1998; Budinger et al., 2006) by

using a confocal laser scanning microscope system

(microscope: Leica DMRXA/TCS4D; xy-motorized stage:

M€arzh€auser, Wetzlar, Germany).

Regions of interest in the Golgi preparations were photo-

graphed by using a digital color camera (Leica DCF500)

mounted on the microscope. All images were arranged and

labeled for figures by using Adobe CS2 Photoshop soft-

ware (Adobe Systems, San Jose, CA). This software was

also used for gray-scale conversion and simple contrast

and brightness enhancement of the Golgi photographs.

RESULTS

The following results originate from small disjunctive

injections of FD and TMRD into different BF locations of

the left AI. The BFs of neurons at the injection sites

ranged from 0.25 kHz to 32 kHz (Table 1, Fig. 1). The

injection sites had a mean diameter of 2566 25 lm (SD)

and usually covered several cortical layers (Table 1). In

the AI, the spatial resolution for frequencies has been

reported to be about 200 lm per octave for high frequen-

cies (>1 kHz) and about 400 lm per octave for low fre-

quencies (<1 kHz) (Scheich et al., 1993; Thomas et al.,

1993). Thus, the injection sites covered a region repre-

senting about one octave in regions of the AI with neuro-

nal BFs > 1 kHz and about half of an octave in regions of

the AI with neuronal BFs < 1 kHz. The distance between

the foci of the FD and TMRD injection sites ranged from

600 lm to 1,100 lm (mean distance 803 6 142 lm).

Consequently, the two injection sites never overlapped

spatially (Table 1).



In each of the tracing experiments, we found numerous

anterogradely labeled axons and their terminations as

well as retrogradely labeled cell bodies in various cortical

areas and subcortical structures. Here, we describe only

the connections of the AI with structures of the auditory

pathway (Rouiller, 1997; Malmierca and Merchan, 2004).

We did not observe any uncommon labeling in the audi-

tory or other brain structures indicating that the dextran

tracers were taken up by fibers of passage or were trans-

ported along distant axon collaterals (Schmued et al.,

1990). Instead, they were taken up specifically by the

neuronal cell bodies (Nance and Burns, 1990) and termi-

nals (Jiang et al., 1993) at the injection sites before being

actively transported along the axons to the terminals (an-

terograde) and somata (retrograde), respectively.

Figure 2. Frontal (A,B, with B at a more caudal level than A), horizontal (C) and sagittal (D) sections through the medial geniculate body

(MGB) and adjacent areas showing the Golgi-structure of the MGB at corresponding section levels as in Fig. 3. The ventral division of the

MGB (MGv) is characterized by its principal bitufted neurons, which form parallel fibrodendritic laminae (white arrowheads) in its lateral

subdivision (pars lateralis, Lv). Within its ovoid medial subdivision (pars ovoidea, Ov), these laminae have a rather circular orientation.

Within the dorsal division of the MGB (MGd), neurons with tufted and radiate dendritic arbors predominate (black arrowheads). The supra-

geniculate nucleus (SG) is characterized by its large stellate neurons (white arrows). Within the medial division of the MGB (MGm), several

neuron types can be found, however, the magnocellular neuron is the most conspicuous one (black arrows). In MGd, SG, rp and MGm,

there is no clear fibrodendritic lamination. For other abbreviations see list. Scale bar = 400 lm in A,C; 200 lm in B,D.

Budinger et al.


Figure 3. Frontal (A,B), horizontal (C), and sagittal (D) sections through the medial geniculate body (MGB) and adjacent areas showing

the dye-labeling patterns in the MGB after injections of FD into high-frequency (hf) AI and of TMRD into low-frequency (lf) AI on the same

side. Panels are at corresponding section levels as in Figure 2. Within the ventral division of the MGB (MGv), a clear topographic arrange-

ment of the anterogradely and retrogradely labeled neuronal elements is obvious in the pars lateralis (Lv) and the pars ovoidea (Ov), but

not in the rostral pole (rp). In the Lv, FD-labeled (hf) fibers and cell bodies of origin are located more medially (A,C), caudally (D), and ven-

trally (A,D) than the TMRD-labeled (lf) fibers and cell bodies. In the Ov, the FD-labeled (hf) fibers and cell bodies are located in more pe-

ripheral layers than the TMRD-labeled (lf) fibers and cell bodies (B). Single-labeled somata in MGv are usually found within the area of the

corresponding anterograde labeling. Double-labeled cell bodies (e.g., arrowheads) are mainly located between the disjunctive FD and

TMRD labeling and in the ventral marginal zone of the MGB (MZMG). Within the MGd, FD- and TMRD-labeled fibers and somata can be

found mainly in its deep dorsal subdivision (DD) but also in all other parts. Differently labeled neuronal elements do not show a clear topo-

graphic arrangement, although there was a trend toward more TMRD-labeled (lf) neuronal elements in caudal aspects of MGd (compare A

with B). The area of single-labeled somata usually slightly exceeds the area of the corresponding anterograde labeling. Double-labeled

somata (arrowheads) can be found throughout the MGd, but particularly in the DD. In the SG, the distribution of FD- and TMRD-labeled

fibers and single- and double-labeled cell bodies (arrowheads) is not topographically ordered. Within the MGm, the distribution of FD- and

TMRD-labeled fibers and cell bodies also does not show any topographic arrangement. In the MGm, the area of labeled cell bodies, which

are often double-labeled (arrowheads), usually exceeds the area of labeled axonal terminations. Note also the anterograde and retrograde

labeling in the brachium of the inferior colliculus (bic) (B–D). White grid lines at the panel’s margins indicate the approximate levels of sec-

tion planes in other panels. The experimental cases, from which tracing data are shown, are identified above the scale bars. For other

abbreviations, see list. (A magenta–green version of this figure has been posted as a supplementary file for the assistance of color-blind

readers.) Scale bar ¼ 400 lm in A,C; 200 lm in B,D.



Labeling patterns in subcortical auditory structures are

shown in Figures 1, 3, 4, and 6–8. For a better under-

standing of their topography, we will illustrate in text and

figures only those experimental cases with FD injections

into high-frequency (hf) regions of the AI and TMRD injec-

tions into low-frequency (lf) regions of the AI. In addition,

for clearer illustration of tracer-labeled neuronal ele-

ments, sections are shown without counterstaining. Sub-

cortical connections of the AI, which are very strong and

topographically organized (i.e., with the MGB, Rt, and IC),

are illustrated in all three standard planes (Figs. 3, 4, 6).

Sparser connections (i.e., with the auditory brainstem)

are illustrated only in the frontal plane (Figs. 7, 8).

Besides anterograde labeling of the corticofugal axons

of AI projecting toward the auditory subcortical nuclei, we

also found retrogradely labeled somata of cells of origin

in the divisions of the MGB and SG and in the bic. Thus,

we will present a description and statistical analysis of

these retrogradely labeled cell bodies (Table 2) and of the

patterns of reciprocity as well.

For an anatomical comparison of the labeling patterns with

the cyto- and fibroarchitecture of the labeled structures and

particularly with the orientation of fibrodendritic laminae, we

Figure 4. Horizontal (A,B), frontal (C), and sagittal (D) sections through the reticular thalamic nucleus (Rt) showing its Golgi architecture

(A) and the dye-labeling patterns after injections of FD into high-frequency (hf) AI and of TMRD into low-frequency (lf) AI on the same side

(B–D). A and B are at corresponding section levels. A: Within the Rt, larger fusiform neurons are usually found in the central Rt (large

arrowheads) and the smaller fusiform neurons (small arrowheads) at its lateral and medial edges. Neurons with round somata are present

throughout the entire nucleus (arrows). The dendritic trees of the fusiform cells arborize mainly perpendicular to the crossing thalamocorti-

cal and corticothalamic fibers (compare with B). B–D: Cortical fibers, passing the internal capsule (ic) toward the thalamus, send off many

short collaterals to the Rt, where they form disk-shaped slabs. FD-labeled (hf) axonal terminations can be found at more medial (B,C), ven-

tral (C,D), and rostral (D) locations than TMRD-labeled (lf) terminations. All other conventions are as in Figure 3. (A magenta–green version

of this figure has been posted as a supplementary file for the assistance of color-blind readers.) Scale bar ¼ 200 lm in A–D.

Budinger et al.


show Golgi preparations at corresponding section levels

(Figs. 2, 4, 5, 7, 8). The Golgi architecture will be described

briefly prior to the description of the labeling patterns (for

more details, see the companion paper: Mylius et al., 2012).

Auditory thalamusMedial geniculate body (MGB).

By means of the Golgi technique, the gerbil’s MGB can

be subdivided into a ventral (MGv), dorsal (MGd), and

medial (MGm) division (Fig. 2). On the ventral and lateral

side, the MGB is surrounded by a marginal zone (MZMG).

In the MGv, three subdivisions are recognizable,

namely, a laminated lateral part (pars lateralis [Lv]), an

ovoid medial part (pars ovoidea [Ov]), and a rostral pole

(rp). The fibrodendritic laminae of Lv, which are formed

by the dendrites of its mainly bitufted neurons, extend

from dorsomedial to ventrolateral in the frontal plane

(Fig. 2A, white arrowheads), from rostromedial to caudo-

lateral in the horizontal plane (Fig. 2C, white arrow-

heads), and from rostrodorsal to caudoventral in the

sagittal plane (Fig. 2D, white arrowheads). The circular

orientation of the fibrodendritic laminae of the Ov is

most obvious at caudal levels in the frontal plane (Fig.

2B) and in sagittal sections (Fig. 2D). Within the rp, no

clear lamination is evident. Within the MGd, at least one

subdivision can be clearly identified, namely, its deep

Figure 5. Frontal (A,B, with B at a more caudal level than A), horizontal (C), and sagittal (D) sections through the inferior colliculi (IC), peri-

collicular tegmental area (Pta), and surrounding regions showing their Golgi structure at corresponding section levels as in Figure 6. Within

the central nucleus of the IC (CIC), the orientation of the fibrodendritic laminae (arrowheads) is based on the orientation of the disk-shaped

principal neurons. The dorsal (DCIC) and external cortex of the IC (ECIC) display a cortex-like architecture with a clear lamination into three

layers (1–3) with increasing cell size and neuronal packing density toward deeper layers. Large multipolar neurons demarcate the border

between layer 3 of the DCIC and ECIC and the CIC (arrows). For other abbreviations, see list. Scale bar ¼ 400 lm in A–D.



dorsal nucleus (DD). A consistent fibrodendritic orienta-

tion of the mainly tufted cells (Fig. 2, black arrowheads)

is not apparent, either in the DD or in the ‘‘remaining’’

MGd. Within the MGm, which is not subdivided, a prefer-

ential orientation of the fibers and dendrites of its vari-

ous neuronal types (e.g., magnocellular neurons; Fig.

2A–C, black arrows) is not evident.

The AI had the strongest subcortical connections with

the subdivisions of the ipsilateral MGv, namely, the Lv

and Ov (Fig. 3). Here, the orientation of the labeled axons

and the distribution of retrogradely labeled somata dis-

played a clear topographic arrangement, which was

related to the injected cortical BF. In addition, the label-

ing patterns closely matched the orientation of the fibro-

dendritic laminae, as seen in the Golgi preparations (Fig.

2), and the tonotopic organization of the MGv as recently

reported for the gerbil (Bauerle et al., 2011).

In the Lv, the FD-labeled (i.e., hf) axons from the AI ter-

minated in its inner, more medial layers, whereas the

TMRD-labeled (i.e., lf) axons from the AI terminated in its

outer, more lateral layers. In addition, there was a caudo-

ventral (hf, FD) to rostrodorsal (lf, TMRD) gradient in the

labeling patterns. The hf and lf projections to the Lv were

always clearly separated, although there was also a small

Figure 6. Frontal (A,B), horizontal (C), and sagittal (D) sections through the inferior colliculi (IC), pericollicular tegmental area (Pta), and

surrounding regions showing the dye-labeling patterns after injections of FD into high-frequency (hf) AI and of TMRD into low-frequency (lf)

AI on the same side. Panels are at corresponding section levels as in Figure 5. The strongest projections from AI terminate in the DCIC

and ECIC; those to the CIC are relatively sparse. The projections to the CIC and DCIC are topographically organized. In the CIC, FD-labeled

(hf) projections from AI terminate in more ventromedial laminae (large arrowheads) than TMRD-labeled (lf) projections, which terminate in

more dorsolateral laminae (small arrowheads). In the DCIC, FD-labeled (hf) projections terminate mainly in its outer layers 1 and 2 (large

arrows), whereas TMRD-labeled (lf) projections terminate mainly in its inner layer 3 (small arrows). In the ECIC and Pta, hf and lf projec-

tions from AI converge in a non-topographic fashion. All other conventions are as in Figure 3. (A magenta–green version of this figure has

been posted as a supplementary file for the assistance of color-blind readers.) Scale bar ¼ 400 lm in A–D.

Budinger et al.


zone of spatial overlap between the FD and TMRD labeling.

In the Ov, the hf projections terminated in its more periph-

eral layers, whereas the lf projections terminated in its

central layers. The zone of spatial overlap of the differently

labeled axons was usually larger in the Ov than in Lv.

Figure 7. Frontal sections through the nuclei of the lateral lemniscus (NLL) and superior olivary complex (SOC). A and C show the Golgi-

structure of the NLL and SOC; B and D show the dye-labeling patterns in the NLL and SOC after injections of FD into high-frequency (hf)

AI and of TMRD into low-frequency (lf) AI on the same side. A and B as well as C and D are at corresponding section levels. A: The dorsal

nucleus of the lateral lemniscus (DNLL) contains a variety of round, multipolar, and elongated cells. At its margins, the dendrites of some

medium-sized and large cells have a somewhat curved orientation parallel to the nuclear boundaries of the DNLL (arrows). The intermedi-

ate nucleus of the lateral lemniscus (INLL) is characterized by diverse multipolar and by many medium-sized horizontally elongated cells

(arrowheads). B: Within the NLL, the majority of labeled fibers can be found at their lateral and medial aspects. In the DNLL, FD-labeled

(hf) axons terminate mainly medioventrally (arrows), whereas TMRD-labeled (lf) axons and their terminations are mainly located laterodor-

sally (arrowheads). In the INLL (and in the VNLL), a topography of the projections from AI is not obvious. C: Within the SOC, the lateral

superior olive (LSO), medial superior olive (MSO), and superior periolivary nucleus (SPN), as well as the medial (MNTB), lateral (LNTB), and

ventral nucleus of the trapezoid body (VNTB) are most conspicuous. In the LSO, the dendrites of the principal neurons form sheets per-

pendicular to the outlines of the LSO (white arrows). In the MSO, dendrites of the principal neurons are oriented horizontally in the frontal

plane (small white arrowheads). The SPN contains some very large multipolar cells (black arrowheads). In the LNTB and VNTB, the den-

drites of several elongated neurons extend in the lateromedial and rostrocaudal direction, respectively (black arrows). D: Within the ipsilat-

eral and contralateral SOC, sparse anterograde tracer labeling can be found throughout the whole nuclear complex (arrows: FD-labeled hf

axons; arrowheads: TMRD-labeled lf axons). Usually, the majority of labeled fibers traverses along the medial and lateral aspects of the

SOC, thereby often making contacts in all major divisions of the SOC. The orientation in A applies to all other panels. Large arrowheads in

C and D point to the midsagittal line. All other conventions are as in Figure 3. (A magenta–green version of this figure has been posted as

a supplementary file for the assistance of color-blind readers.) Scale bar ¼ 400 lm in A–D.



Within the MGv, retrogradely labeled somata of cells

projecting to the AI were distributed among the antero-

gradely labeled fibers descending from the AI. We found

an average number of 2,856 6 986 (range, 1,747–5,132)

labeled cell bodies in the MGv (Table 2), which comprised

78.2% of all labeled auditory subcortical neurons (see Fig.

9). The majority of these cell bodies were single labeled

(96.5%) and distributed in a largely topographic manner:

Cells projecting toward the hf AI were mainly located in

the medial layers of the Lv and peripheral layers of the

Ov, whereas cells projecting toward the lf AI were mainly

located in the lateral layers of the Lv and central layers of

the Ov. There was a large spatial overlap of the region of

retrograde labeling with the region of anterograde label-

ing, indicating a high degree of reciprocity in the thalamo-

cortical and corticothalamic connections between the

MGv and AI. However, the region of the anterograde

labeling usually slightly exceeded the region of retrograde

labeling in the MGv, and there were always a few single-

labeled somata at non-matched locations (similar in rat:

Winer and Larue, 1987; mouse: Llano and Sherman,

2008; cat: Winer et al., 2001; Lee et al., 2004a,b; Lee and

Winer, 2008).

Within the Lv, double-labeled cell bodies (Fig. 3, white

arrowheads) were found mainly between the areas of FD

and TMRD label. Within the Ov, the distribution of double-

labeled cell bodies was wider. In the transition area

between the Lv and Ov and in the ventral MZMG, double-

labeled cell bodies were usually also found. The percent-

age of double-labeled cell bodies within the MGv

depended neither on the size of the injection sites in the

hf AI and lf AI nor significantly on their distance (Table 1).

Nevertheless, there was a positive but still not statisti-

cally significant (P ¼ 0.126; Pearson correlation test)

trend for more closely located injection sites in the AI to

yield more double-labeled cell bodies in the MGv. The dis-

tance dependence may have become significant if we

had performed partially overlapping FD and TMRD injec-

tions into the AI, because this would have produced a

larger number of double-labeled somata in the MGv. How-

ever, it was actually the aim of this study to avoid overlap-

ping injection sites in order not to miss possible topogra-

phies of the subcortical targets.

Within the MGd, the strongest anterograde labeling

was found in the DD (Fig. 3). The overall labeling in the

MGd was not as intense as in the MGv, which is consist-

ent with previous evidence that the main cortical projec-

tion to the MGd is from the posterior auditory fields DP

and VP (Budinger et al., 2000b). A clear-cut topographic

segregation of the differently labeled axons was not evi-

dent, although hf fibers tended to terminate in more

Figure 8. Sagittal sections through the cochlear nuclear complex showing its Golgi-structure (A) and the dye-labeling patterns after injec-

tions of FD into high-frequency (hf) AI and of TMRD into low-frequency (lf) AI on the same side (B). A and B are at corresponding section

levels. A: Within the spherical cell area (sca) of the anteroventral cochlear nucleus (AVCN), spherical bushy cells predominate (white

arrows). Within the posteroventral cochlear nucleus (PVCN), globular bushy cells (globular cell area [gca]; white arrowheads) and octopus

cells (octopus cell area [oca]; black arrows) are in the majority. The four layers of the dorsal cochlear nucleus (DCN) display a variety of

neuron types including pyramidal cells in layer 2 (black arrowheads). B: Within the CN, only a few FD-labeled (hf) (arrows) and TMRD-la-

beled (lf) terminations (arrowhead) can be found. They are mainly located in the DCN and superficial granule cell layer (sgcl). Some fibers

are labeled in the PVCN, close to the border with the deep layers of the DCN, and in the sca of the AVCN. The orientation in A also

applies to B. All other conventions are as in Figure 3. (A magenta–green version of this figure has been posted as a supplementary file for

the assistance of color-blind readers.) Scale bar ¼ 400 lm in A,B.

Budinger et al.


TABLE 2.

Subcortical Auditory Inputs Into the Primary Auditory Field (AI)1

Numbers

MGv MGd SG MGm bic

hf lf Double All hf lf Double All hf Lf Double All hf lf Double All hf lf Double All

G145 1,265 956 218 2,439 216 168 122 506 24 18 31 73 31 14 21 66 18 5 18 41G146 1,027 1,253 155 2,435 127 235 167 529 21 35 18 74 57 71 65 193 11 25 14 50G147 1,395 1,090 75 2,560 212 201 62 475 37 18 19 74 56 32 31 119 29 26 9 64G148 1,657 1,747 72 3,476 291 319 50 660 33 50 11 94 44 51 46 141 17 14 10 41G148 1,227 1,858 41 3,126 267 352 39 658 10 27 8 45 53 62 28 143 14 13 8 35G150 1,050 1,489 45 2,584 256 399 46 701 15 28 8 51 47 39 17 103 11 19 5 35G155 869 1,052 96 2,017 181 214 63 458 23 36 24 83 22 38 23 83 21 26 13 60G156 796 929 27 1,752 156 176 33 365 16 32 11 59 24 46 21 91 12 15 7 34G162 1,698 1,819 89 3,606 247 285 80 612 20 26 10 56 27 20 23 70 16 12 9 37G164 1,341 1,691 90 3,122 156 182 68 406 24 33 21 78 29 35 25 89 19 25 3 47G190 780 899 68 1,747 155 250 54 459 10 19 16 45 21 16 25 62 8 12 2 22G191 780 1,014 44 1,838 278 180 26 484 38 34 11 83 19 44 21 84 4 6 3 13G213 2,012 1,956 176 4,144 387 397 164 948 64 58 22 144 45 36 49 130 19 18 8 45G214 2,313 2,663 156 5,132 276 396 92 764 22 73 21 116 33 62 38 133 17 25 1 43Mean 1,300.71 1,458.29 96.57 2,855.57 228.93 268.14 76.14 573.21 25.50 34.79 16.50 76.79 36.29 40.43 30.93 107.64 15.43 17.21 7.86 40.50SD 476.67 519.83 57.74 985.72 70.83 88.82 45.25 159.60 14.09 15.79 6.93 27.59 13.62 17.23 13.75 37.18 6.15 7.35 4.90 13.32

Percentages

MGv MGd SG MGm bic

hf lf Double All hf lf Double All hf lf Double All hf lf Double All hf lf Double All

G145 51.87 39.20 8.94 100 42.69 33.20 24.11 100 32.88 24.66 42.47 100 46.97 21.21 31.82 100 43.90 12.20 43.90 100G146 42.18 51.46 6.37 100 24.01 44.42 31.57 100 28.38 47.30 24.32 100 29.53 36.79 33.68 100 22.00 50.00 28.00 100G147 54.49 42.58 2.93 100 44.63 42.32 13.05 100 50.00 24.32 25.68 100 47.06 26.89 26.05 100 45.31 40.63 14.06 100G148 47.67 50.26 2.07 100 44.09 48.33 7.58 100 35.11 53.19 11.70 100 31.21 36.17 32.62 100 41.46 34.15 24.39 100G148 39.25 59.44 1.31 100 40.58 53.50 5.93 100 22.22 60.00 17.78 100 37.06 43.36 19.58 100 40.00 37.14 22.86 100G150 40.63 57.62 1.74 100 36.52 56.92 6.56 100 29.41 54.90 15.69 100 45.63 37.86 16.50 100 31.43 54.29 14.29 100G155 43.08 52.16 4.76 100 39.52 46.72 13.76 100 27.71 43.37 28.92 100 26.51 45.78 27.71 100 35.00 43.33 21.67 100G156 45.43 53.03 1.54 100 42.74 48.22 9.04 100 27.12 54.24 18.64 100 26.37 50.55 23.08 100 35.29 44.12 20.59 100G162 47.09 50.44 2.47 100 40.36 46.57 13.07 100 35.71 46.43 17.86 100 38.57 28.57 32.86 100 43.24 32.43 24.32 100G164 42.95 54.16 2.88 100 38.42 44.83 16.75 100 30.77 42.31 26.92 100 32.58 39.33 28.09 100 40.43 53.19 6.38 100G190 44.65 51.46 3.89 100 33.77 54.47 11.76 100 22.22 42.22 35.56 100 33.87 25.81 40.32 100 36.36 54.55 9.09 100G191 42.44 55.17 2.39 100 57.44 37.19 5.37 100 45.78 40.96 13.25 100 22.62 52.38 25.00 100 30.77 46.15 23.08 100G213 48.55 47.20 4.25 100 40.82 41.88 17.30 100 44.44 40.28 15.28 100 34.62 27.69 37.69 100 42.22 40.00 17.78 100G214 45.07 51.89 3.04 100 36.13 51.83 12.04 100 18.97 62.93 18.10 100 24.81 46.62 28.57 100 39.53 58.14 2.33 100Mean 45.38 51.15 3.47 100 40.12 46.46 13.42 100 32.19 45.51 22.30 100 34.10 37.07 28.83 100 37.64 42.88 19.48 100SD 4.24 5.37 2.09 0 7.24 6.59 7.32 0 9.27 11.43 8.86 0 8.15 9.89 6.61 0 6.36 11.90 10.30 01Number and percentages of retrogradely labeled somata in structures of the auditory pathway after injections of fluorescein-labeled (FD) and tetramethylrhodamine-labeled dextran (TMRD) into high-fre-

quency (hf) AI and low-frequency (lf) AI of the gerbil. Structures include the divisions of the medial geniculate body (MGB; ventral MGv, medial MGm, dorsal MGd) and suprageniculate nucleus (SG) as well as

the brachium of the inferior colliculus (bic). The upper table provides the separate numbers of FD- (green boxes), TMRD- (red boxes), and double-labeled somata (yellow boxes) as well as their total (white

boxes), respectively, in these structures. The lower table provides the relative percentage of FD-, TMRD-, and double-labeled somata on the total of all labeled somata in these structures, which always add

up to 100% (white boxes). Data are provided for each experimental animal and for the mean 6 1 standard deviation (SD) across animals.

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rostral aspects of the MGd than lf fibers (compare Figs.

3A and B).

Within the MGd, the strongest retrograde labeling was

also found in the DD. As in the MGv, the anterograde

and retrograde labeling in the MGd was largely overlap-

ping, indicating a high degree of reciprocity in the con-

nections between the MGd and AI. However, in contrast

to the MGv, the area of labeled cell bodies slightly

exceeded the area of anterograde labeling in the MGd.

We found an average number of 573 6 160 (range,

365–948) retrogradely labeled somata in the MGd (Ta-

ble 2), which constituted 15.7% of all labeled auditory

subcortical neurons projecting to the AI (see Fig. 9).

There were significantly more double-labeled somata in

the MGd (13.4%) than in the MGv (3.5%). (One-way

between-group analysis of variance [ANOVA] showed

that the main effect of MGB subdivisions is significant

(F(4,65) ¼ 22.53, P < 0.0001). Further post hoc Stu-

dent’s t-tests revealed that the percentage of double-la-

beled cell bodies in the MG is significantly smaller than

that in the MGv (P ¼ 0. 0002)]. The regions of single FD-

and TMRD-labeled cell bodies showed a topography sim-

ilar to those of the descending fibers from the AI: neu-

rons projecting to the hf AI were most frequently found

in rostral aspects of the MGd, whereas neurons projec-

ting to the lf AI were most frequently found in caudal

aspects of the MGd (compare Figs. 3A and B). As in the

MGv, there was a positive but statistically insignificant

trend (P ¼ 0.085; Pearson) for more closely located

injection sites in the AI to yield more double-labeled cell

bodies in the MGd.

Within the MGm, we consistently found FD- and TMRD-

labeled fibers after injections into the AI (Fig. 3). The over-

all labeling in the MGm was not as strong as in the MGv,

supporting previous results that the MGm is the main cor-

ticothalamic target of the anterior field AAF in the gerbil

(Budinger et al., 2000b). The differently labeled fibers

from the AI overlapped within the MGm and thus did not

show any topographic arrangement.

The degree of spatial reciprocity in the connections

between the MGm and AI was the least of all the geni-

culo-cortico-geniculate connections because the area of

retrogradely labeled somata notably exceeded the area of

anterogradely labeling in the MGm. We found an average

number of 108 6 37 (range, 62–133) retrogradely la-

beled cell bodies of origin in the MGm (Table 2), which

represented 2.9% of all labeled auditory subcortical neu-

rons (see Fig. 9). The MGm showed the highest percent-

age of double-labeled somata (28.8%) of all MGB divisions

(P < 0.037, Student’s t-test). There was also no topo-

graphic arrangement of either single- or double-labeled

cell bodies of origin. There was no statistically significant

correlation between the distance of the injection sites in

the hf AI and lf AI and the number of double-labeled

somata in MGm (P ¼ 0.271; Pearson).

Suprageniculate nucleus (SG).Medially, the MGB is bordered by the SG, which in

some anatomical studies (rat: Clerici et al., 1990; Winer

et al., 1999) is considered a subdivision of the MGd. In

Golgi staining, the SG is characterized by its large stellate

neurons (Fig. 2A,B; white arrows).

Within the SG, the projections from the hf AI and lf AI

always spatially overlapped, thus converging in a non-

topographic manner (Fig. 3). Comparable to the labeling

pattern in the MGd, the anterograde and retrograde

Figure 9. Summary diagram of the corticofugal and thalamocorti-

cal sytems of the gerbil’s primary auditory cortex (AI) as estab-

lished in the present study by the anterograde and retrograde

axonal transport of the bidirectional tracers FD and TMRD. Each

box represents a brain structure, which is connected with AI. Dif-

ferent thicknesses of lines and arrows are used to indicate the

relative strength of a connection. Presumably tonotopic connec-

tions are colored in red. For thalamocortical connections, the per-

centage of retrogradely labeled somata in the divisions of the

medial geniculate body (MGv, d, m), the suprageniculate nucleus

(SG), and the brachium of the inferior colliculus (bic) are given.

Other connections, in particular with contralateral auditory hind-

brain structures, are likely but were not established here due to

the focal tracer injections into AI. For other abbreviations, see

list. (A magenta–green version of this figure has been posted as

a supplementary file for the assistance of color-blind readers.)

Budinger et al.


labeling in the SG largely overlapped; however, the area

of retrogradely labeled somata slightly exceeded the area

of anterograde labeling. We found an average number of

77 6 28 (range, 45–144) retrogradely labeled cell bodies

in the SG (Table 2), which constituted 2.1% of all labeled

auditory subcortical neurons (see Fig. 9). The percentage

of double-labeled somata in the SG (22.3%) was signifi-

cantly higher than in the MGd (13.4%) (P ¼ 0.008; Stu-

dent’s t-test). In the SG, there was no topographic

arrangement of single and double-labeled cell bodies of

origin. There was also no statistically significant correla-

tion between the distance of the injection sites in the hf

AI and lf AI and the number of double-labeled somata in

the SG (P¼ 0.342; Pearson).

Reticular thalamic nucleus (Rt).The auditory sector of the Rt is located in the caudo-

ventral region of the nucleus (Crabtree, 1998; Budinger

et al., 2000b) and is closely related to the (mainly de-

scending) auditory pathway (Rouiller, 1997). The neurons

of the Rt include rather small cells with round somata and

and cells of variable size with fusiform somata (Fig. 4A).

The dendritic trees of the fusiform cells arborize mainly

perpendicular to the crossing thalamocortical and corti-

cothalamic fibers.

We noted strong projections from the AI to the auditory

sector of the ipsilateral Rt. Here, the corticothalamic FD-

and TMRD-labeled fibers gave off short collaterals, which

terminated in largely non-overlapping regions of the Rt

(Fig. 4B–D). They formed disk-shaped slabs, which were

oriented perpendicular to the corticothalamic fibers and

thus parallel to the dendritic orientation of most Rt neu-

rons. The slabs formed by the hf AI projection fibers were

generally found more medially (Fig. 4B,C), ventrally (Fig.

4C,D), and somewhat more rostrally (Fig. 4D) than the

slabs formed by the lf AI projection fibers.

Auditory midbrainInferior colliculi (IC).

Within the gerbil’s IC, three principal divisions can be

distinguished: a central nucleus (CIC), a dorsal cortex

(DCIC), and an external cortex (ECIC) (Fig. 5). The CIC is

also bordered by a group of paracentral tectal nuclei

(PTN) including a dorsomedial nucleus (DM). On the ven-

tral side, the IC is bordered by the pericollicular tegmen-

tal area (Pta) including the cuneiform nucleus (Cu), the

nucleus sagulum (Sag), and the nucleus of the brachium

of the IC (bic).

Within the CIC, the disk-shaped cells form conspicuous

fibrodendritic laminae, which are oriented from dorsome-

dial to ventrolateral in frontal sections (Fig. 5A,B, arrow-

heads), from rostromedial to caudolateral in horizontal

sections (Fig. 5C, arrowheads), and from caudodorsal to

rostroventral in sagittal sections (Fig. 5D, arrowheads).

The DCIC and ECIC display a cortex-like architecture with

a clear lamination into three layers.

The IC was the main target of mesencephalic projections

from AI (Fig. 6). On the ipsilateral side, axons terminated in

the DCIC and ECIC and, to a lesser degree, in the CIC. Sev-

eral paracentral tectal and tegmental nuclei, including the

bic, Sag, and Cu, were also targeted by projections from AI.

Axons passing through the commissure of the IC (cic) termi-

nated mainly in the contralateral DCIC and ECIC and very

sparsely in the contralateral CIC (not shown). The contralat-

eral projection pattern in the IC was symmetrical to the ipsi-

lateral one but not so intensive. In the CIC and DCIC, the

FD- and TMRD-labeled axons terminated in largely non-over-

lapping regions, which corresponded to the laminar (Fig. 5)

as well as tonotopic organization of the IC in the gerbil

(Ryan et al., 1982; Melzer, 1984; Bruckner and Rubsamen,

1995; Heil et al., 1995; Harris et al., 1997). In the CIC, the

terminating fibers from AI were oriented in a dorso-caudo-

medial to ventro-rostro-lateral direction parallel to its fibro-

dendritic laminae. Labeled axons from the hf AI and their

collaterals were located more ventromedially (Fig. 6, large

arrowheads) than axons from the lf AI (Fig. 6, small arrow-

heads). Fibers targeting the CIC always appeared as a con-

tinuation from the DCIC projections. In the DCIC, the hf

fibers from the AI terminated more peripherally, i.e., in the

outer (1) and middle (2) layers (Fig. 6, large arrows), than

the lf fibers, which terminated mainly in the middle (2) and

inner (3) layers of the DCIC (Fig. 6, small arrows).

Within the ipsilateral bic, we consistently found retro-

gradely labeled somata of cells of origin (Fig. 3B–D). The

area covered by these somata notably exceeded the area

of anterograde labeling. We found an average number of

40 6 13 (range, 13–64) retrogradely labeled somata in

the bic (Table 2), which constituted 1.1% of all labeled au-

ditory subcortical neurons projecting toward the AI (see

Fig. 9). Out of the labeled somata in the bic, 19.5% were

double-labeled. There was no topographic arrangement

of the labeled somata and no statistically significant cor-

relation between the distance of the injection sites and

the number of double-labeled somata in the bic (P ¼0.207; Pearson).

Auditory hindbrainConnections of the AI with auditory structures of the

metencephalon were only of a descending nature and tar-

geted the nuclei of the lateral lemniscus (NLL) ipsilaterally,

the superior olivary complex (SOC) bilaterally, and the

cochlear nuclear complex (CN) ipsilaterally via the cerebral

peduncle (cp), pyramidal tract (py), and trapezoid body

(tb). In contrast to previous studies on rat and guinea pig

(Feliciano et al., 1995; Weedman and Ryugo, 1996a; Muld-

ers and Robertson, 2000; Jacomme et al., 2003; Coomes



and Schofield, 2004; Schofield and Coomes, 2005), we

found only a few labeled axons in the auditory hindbrain

structures. This was most likely due to the relatively small

tracer injections into the gerbil’s AI in the present study

and to the fact that these projections exclusively originate

from the deep layers of the AC, which were not entirely

covered by our injections (Table 1).

Nuclei of the lateral lemniscus (NLL).Three divisions of the NLL can be distinguished,

namely, a dorsal (DNLL), an intermediate (INLL), and a

ventral (VNLL) nucleus. The latter can be further subdi-

vided into a ventral (vVNLL) and a dorsal part (dVNLL).

The DNLL contains a variety of cell types; a clear fibroden-

dritic lamination of this nucleus is not always evident, but at

its margins the dendritic fields of several elongated neurons

have a curved orientation parallel to its nuclear boundaries

(Fig. 7A, arrows). The INLL and VNLL are characterized by

various multipolar cell types, which form either rather loose

(dVNLL) or compact (INLL, vVNLL) cell populations.

At the level of the NLL, most labeled axons were found at

the lateral surface and at the border region with paralemnis-

cal areas. From these regions they also entered the three

main divisions of the NLL, namely, the DNLL, INLL, and

VNLL. Within the DNLL, the majority of hf axons terminated

in its medioventral aspect, whereas lf axons terminated

mainly in its laterodorsal aspect (Fig. 7B). Many of the hf and

lf projections from the AI terminated parallel to the curved

laminae formed by the elongated cells of the DNLL. Projec-

tions from the AI to the INLL and VNLL were mainly collater-

als of labeled fibers, which passed the NLL medially and lat-

erally. There was no obvious topographic arrangement of the

labeled fibers related to the injected BF in the AI, neither of

their trajectory nor of the termination patterns.

Superior olivary complex (SOC).By means of the Golgi technique, six divisions of the ger-

bil’s SOC can be reliably delineated on the basis of theirrather compact cellular organization. These include the lat-eral (LSO) and medial (MSO) superior olive, the medial(MNTB), lateral (LNTB), and ventral (VNTB) nucleus of the tra-pezoid body as well as the superior periolivary nucleus (SPN)(Fig. 7C). Various other, more loosely organized periolivarycell groups surround them and are difficult to distinguishfrom each other in Golgi preparations (for further descrip-tions, see Budinger et al., 2000b; Mylius et al., 2012).

A small but consistent number of axons and terminals

was found in the ipsilateral and contralateral SOC (Fig.

7D). Generally, the ipsilateral projection from the AI was

more intense than the contralateral one. Most labeled

fibers traveled along the dorsomedial and ventral margins

of the SOC. They sent off collaterals, which mainly termi-

nated in the medial LSO, SPN, and MNTB as well as in the

LNTB and VNTB. In addition, very few fibers were found in

the MSO and adjacent periolivary nuclei. A topography of

the projections from the AI to the SOC, related to the

injected cortical BF, was not evident. Again, this may be

due to the limited number of labeled fibers.

Cochlear nuclei (CN).The cochlear nuclear complex of the gerbil consists of

three main divisions, namely, a laminated dorsal (DCN)

and two rather compact ventral nuclei: the anteroventral

(AVCN) and the posteroventral (PVCN) nucleus (Fig. 8A).

There were very sparse projections from the AI to the

ipsilateral CN (Fig. 8B). The labeled fibers made contacts

in the DCN including the superficial granule cell layer

(sgcl), which covers the dorsal and lateral surface of the

ventral nuclei. Other fibers were found in the PVCN close

to the border with the deep layers of the DCN. Single

fibers were also seen in the spherical cell area (sca) of

the AVCN. Due to the limited number of labeled fibers,

we did not see a topography related to the injected BF in

AI.

DISCUSSION

In the present study, we investigated the frequency-

related topography of connections of the primary auditory

field (AI) in the Mongolian gerbil with subcortical struc-

tures of the auditory system. By means of parallel injec-

tions of two different bidirectional tracers (FD and TMRD)

into two different frequency representations of the AI, we

analyzed the spatial distribution of the differently labeled

axonal projections and somata of cells of origin within the

connected structures. A summary of the established con-

nections is given in Figure 9.

We then compared the anterograde and retrograde

labeling patterns with the architecture of the gerbil’s au-

ditory subcortical nuclei as seen by means of the Golgi-

staining technique presented here and in our companion

paper (Mylius et al., 2012) and as known from previous

studies on the cyto-, fibro-, and chemoarchitecture of the

gerbil’s auditory pathway (for references, see Materials

and Methods). We also compared our results with the

known representations of acoustic frequencies in the au-

ditory pathway of the gerbil (for references, see next sec-

tion). Thus our conclusions on the tonotopy of AI connec-

tions were based on the following evidence:

1. Tracer injections were largely made into physiologi-

cally verified BF representation areas of the AI.

2. A tonotopic organization of a structure is most fre-

quently accompanied by a topographic arrangement

of the representing neurons (place principle; von

Helmholtz, 1863; von Bekesy, 1960). Thus, a topo-

graphic relationship between the injection sites and

the differentially labeled neuronal elements most

Budinger et al.


likely reflects tonotopic connections between the

injected and labeled structures (Andersen et al.,

1980a; Calford and Aitkin, 1983; Brandner and

Redies, 1990; Hu, 2003; Velenovsky et al., 2003;

Hackett et al., 2011).

3. Along this line of evidence, neurons of the same or

similar BF are often located in the same microstruc-

ture, such as (fibrodendritic) layers or cortical col-

umns (for review, see Oliver and Huerta, 1992;

Schwartz, 1992; Read et al., 2002; Cetas et al.,

2003; Linden and Schreiner, 2003; Winer, 2011).

Consequently, labeling patterns, which match in size

and orientation these mesoscopical structures (here

in particular the fibrodendritic laminae of the MGB,

Rt, IC, and DNLL) most likely reflect the tonotopic

inputs and outputs of these neurons.

4. Finally and ideally, the topography of the labeled

neuronal elements matches directly the known tono-

topic organization of these structures.

We conclude that 1) the AI of the gerbil has mainly

topographic, i.e., tonotopic connections with structures

of the auditory core (tonotopic, lemniscal) pathway as

well as with tonotopically organized structures, which are

rather assigned to the non-lemniscal pathway (MGd, Rt,

and DCIC); and 2) in addition, there are substantial but

not topographically organized (non-tonotopic) connec-

tions with non-tonotopically organized structures of the

non-lemniscal pathway. This shows that the AI is not only

a major part of the tonotopic core auditory system, as al-

ready demonstrated for other species (for review, see

Rouiller, 1997; Hackett, 2011), but also interacts sub-

stantially with structures of the non-lemniscal system in a

tonotopic and non-tonotopic manner.

Corticofugal and thalamocorticalconnections of AI in gerbils andcomparisons with other mammalsAuditory thalamus.

Within two subdivisions of the MGv, namely, the Lv and

Ov, the topographic distribution of the differently labeled

corticothalamic terminations as well as of the thalamo-

cortical cells of origin mimics the arrangement of the cel-

lular layers in these subdivisions. It also matches the the

topography of collicular inputs into the MGv (Cant and

Benson, 2007) and the tonotopic gradient of frequency-

representation in the MGv as recently reported for the

gerbil (Bauerle et al., 2011). On the basis of this evidence,

we suggest that the low-to-high frequency gradient within

the gerbil’s MGv runs from rostro-dorso-lateral to caudo-

ventro-medial in the Lv and from central to peripheral in

the Ov and that there is a strict frequency match (tono-

topy) of the core thalamo-cortico-thalamic connectivities.

The latter assumption is also supported by the low per-

centage of double-labeled cell bodies of origin in the MGv

(3.5%).

Strong evidence for strict tonotopic connections

between the AI and MGv also comes from combined elec-

trophysiological mapping and anatomical tracing studies on

other mammals including cat (thalamocortical connections:

Middlebrooks and Zook, 1983; Imig and Morel, 1984;

Rodrigues-Dagaeff et al., 1989; Rouiller et al., 1989; Brand-

ner and Redies, 1990; He, 1997; Lee et al., 2004b; Read

et al., 2008; corticothalamic connections: Rouiller and de

Ribaupierre, 1985; Bajo et al., 1995; Takayanagi and Ojima,

2006), rabbit (thalamocortical: Velenovsky et al., 2003), rat

(thalamocortical: Storace et al., 2011), and mouse (thala-

mocortical: Hackett et al., 2011). However, there are also

always a few connections in the gerbil, which obviously do

not connect frequency-matched neuronal populations. This

is indicated by corticothalamic projections, which diverge

slightly into neighboring frequency representation areas,

and by ‘‘mismatched’’ cells of origin (similar in rat: Winer

and Larue, 1987; mouse: Llano and Sherman, 2008; and

cat: Winer et al., 2001; Lee et al., 2004a,b; Takayanagi and

Ojima, 2006; Lee and Winer, 2008). This issue has not

been systematically investigated, but one clue could be the

local heterogeneity of auditory cortical neurons shown by

high-resolution two-photon calcium imaging of the supra-

granular layers of the mouse auditory cortex (Bandyopad-

hyay et al., 2010; Rothschild et al., 2010). Whereas on a

large scale, as covered by our injection sites in the AI, neu-

rons show the same frequency selectivity, the tonotopy

may be fractured on a fine scale, which might be reflected

in the ‘‘mismatched’’ tracer labeling.

Compared to the MGv, the connections of the AI with

the MGd are more diffuse, and there are more double-la-

beled somata in the MGd (13.4%). Still, the connections

show a slight topographic organization: the lf representa-

tion of the AI is preferentially connected with the caudal

MGd and the hf representation with the rostral MGd. Sim-

ilar topographies have been reported by tracing studies in

the rat (Roger and Arnault, 1989; Hazama et al., 2004).

Whether the MGd is indeed tonotopically organized has

not yet been electrophysiologically tested in gerbils and

could not be clearly confirmed in rats (Bordi and LeDoux,

1994a) or in other species (cat: Calford and Webster,

1981; Imig and Morel, 1985b; Morel et al., 1987; and

guinea pig: Redies and Brandner, 1991; Anderson et al.,

2007; Zhang et al., 2008).

The connections of the AI with the MGm in the gerbil

do not show a topographic organization and thus are

most likely non-tonotopic. This assumption is also sup-

ported by the high percentage of double-labeled cell

bodies in the MGm (28.8%) compared to all other MGB

divisions. Non-tonotopic connections between the AI and



MGm are compatible with electrophysiological studies

that report neurons in the MGm to be widely tuned to

tones without displaying a clear tonotopy as in the MGv

(cat: Phillips and Irvine, 1979; Calford, 1983; Imig and

Morel, 1984; Morel et al., 1987; Rouiller et al., 1989; rat:

Bordi and LeDoux, 1994a; and guinea pig: Redies and

Brandner, 1991; Anderson et al., 2007; Zhang et al.,

2008) and to process other sensory stimuli as well (Wep-

sic, 1966; Khorevin, 1978; Bordi and LeDoux, 1994b;

Komura et al., 2005).

The overlapping projections from the lf and hf AI and

the high number of double-labeled somata of cells of ori-

gin in the SG (22.3%) suggest that the connections of AI

with the SG in the gerbil are most likely non-tonotopic.

This is compatible with the non-tonotopic organization of

the SG and the broad frequency tuning of its acoustically

responsive neurons (rat: Bordi and LeDoux, 1994a;

guinea pig: Anderson et al., 2007; and cat: Morel et al.,

1987; Benedek et al., 1997). Frequency-specific input

may not be required in the SG because its neurons are

also to a large extent responsive to visual, vestibular, and

somatosensory stimulation (rat: Bordi and LeDoux,

1994b; and cat: Hicks et al., 1986; Benedek et al., 1997)

and might be strongly involved in multisensory processing

(Budinger et al., 2006).

In the gerbil, we found that the projections from the AI

to the auditory sector of the Rt are topographically organ-

ized. Fibers from the lf AI terminate more latero-dorso-

caudally in the Rt, whereas fibers from the hf AI terminate

more medio-ventro-rostrally. The orientation of the termi-

nal fields, which is more or less perpendicular to the

fibers passing the Rt, corresponds to the orientation of

the dendritic fields of the larger fusiform neurons within

this nucleus (Mylius et al., 2012). We suggest that the

layers formed by these neurons underlie a tonotopic orga-

nization of the Rt in the gerbil, although it has not yet

been probed electrophysiologically. In the rat, cat, and

guinea pig, neurons of the Rt respond well to pure tones

(Shosaku and Sumitomo, 1983; Imig and Morel, 1985a;

Villa, 1990; Simm et al., 1990; Xu et al., 2007) and are

roughly arranged along a large-scale tonotopic gradient

(Villa, 1990; Cotillon-Williams et al., 2008). Further sup-

port for a tonotopic organization of the Rt comes from

rats (Rouiller and Welker, 1991; Hazama et al., 2004;

Kimura et al., 2012) and galagos (Conley et al., 1991), in

which a topography of the auditory cortico-reticular-tha-

lamic connections was also established.

Auditory midbrain.In the gerbil, corticocollicular fibers terminate in all

divisions of the ipsilateral IC and to a lesser degree also

in the contralateral IC (Budinger et al., 2000b; Bajo and

Moore, 2005). The projections of the lf and hf AI to the

CIC terminate in parallel to the orientation of its fibroden-

dritic laminae, which run from dorso-caudo-medial to ven-

tro-rostro-lateral. Neurons within the dorsal laminae rep-

resent the lowest frequencies, and neurons within the

ventral laminae represent the highest frequencies of the

animal’s audible range, as shown by electrophysiological

and metabolic (2-deoxyglucose) mapping studies in the

gerbil (Ryan et al., 1982; Melzer, 1984; Bruckner and

Rubsamen, 1995; Heil et al., 1995; Harris et al., 1997)

and in other mammals (for review, see Oliver and Huerta,

1992). Likewise, descending projections from the AI to

the CIC were also documented in most of these species

to be tonotopically arranged (rat: Herrera et al., 1994;

Saldana et al., 1996; ferret: Bajo et al., 2007; cat: Ander-

sen et al., 1980b; monkey: Luethke et al., 1989; and

guinea pig: Lim and Anderson, 2007).

In the DCIC, the corticocollicular axons originating

from the hf AI terminate preferentially in its outer layers 1

and 2, whereas axons from the lf AI terminate preferen-

tially in its deeper layer 3, which borders the dorsal lf lam-

inae of the CIC. Although in the gerbil a tonotopic organi-

zation of the DCIC has not been described (Bruckner and

Rubsamen, 1995; Heil et al., 1995; Harris et al., 1997),

the corticocollicular termination pattern in the gerbil

matches the tonotopic gradient across the layers of the

DCIC found in cat. Here, the tonotopic organization of the

DCIC was reported to roughly mirror-image the organiza-

tion of the CIC (Rose et al., 1963; Merzenich and Reid,

1974; Aitkin et al., 1975; Serviere et al., 1984). Corre-

spondingly, a tonotopy in the corticocollicular projection

pattern from the AI to the DCIC was found in cat (Ander-

sen et al., 1980b) and also in rat (Herbert et al., 1991;

Herrera et al., 1994; Saldana et al., 1996).

In the gerbil, the projections to the ECIC and pericollicu-

lar tectal and tegmental areas (including the bic, Sag, and

Cu) do not show any frequency-related topographic

arrangement and appear rather diffuse. This pattern most

likely reflects the non-tonotopic organization and the multi-

sensory influences converging onto these nuclei (rat: Kelly

et al., 1998a; rabbit: Pascoe and Kapp, 1993; cat: Kudo

et al., 1984; Beneyto et al., 1998; and ferret: Schnupp and

King, 1997). In the gerbil, the bic also projects directly to

the AI in a non-topographic and rather diverging manner

(19.5% double-labeled cell bodies of origin). The functions

of the direct connections between the AI and bic remain

largely unknown but may involve spatial orientation behav-

ior (Schnupp and King, 1997) and auditory-motor adjust-

ments (Beneyto et al., 1998; Winer et al., 1998).

Our findings on the gerbil’s corticocollicular con-

nectivities are in good agreement with a previous

study on the gerbil using injections of retrograde trac-

ers into the IC and of an anterograde tracer into the

Budinger et al.


auditory core fields AI and AAF (Bajo and Moore,

2005). These authors also found the strongest con-

nections between the auditory cortical core and the

ipsilateral DCIC and ECIC and overall weaker connec-

tions with the CIC and the contralateral side. Projec-

tions to the CIC were also reported to be topographi-

cally organized, although they were generally stronger

than in our experimental cases. This might be due to

some technical differences (e.g., larger injection sites

into the CIC), but also to differences in the parcella-

tion of the IC. In particular, we assigned the most dor-

sal part of the CIC as seen by Bajo and Moore (2005),

rather to the deep layer 3 of the DCIC (for a detailed

discussion, see Mylius et al., 2012).

Auditory hindbrain.Corticofugal projections to subcollicular structures of

the auditory pathway are relatively sparse and thus are

detectable only after large tracer injections into the audi-

tory cortex (rat/mouse: Feliciano et al., 1995; Weedman

and Ryugo, 1996a; Mulders and Robertson, 2000; Meltzer

and Ryugo, 2006; guinea pig: Jacomme et al., 2003;

Coomes and Schofield, 2004; Schofield and Coomes,

2005) or its respective subcortical targets (rat: Weedman

and Ryugo, 1996b; Doucet et al., 2002; guinea pig: Scho-

field et al., 2006). Consequently, these projections are

difficult to investigate using smaller injections into re-

stricted frequency representations of the AI as performed

in our study. Despite these experimental limitations, we

were able to show in the gerbil that the corticolemniscal

projections from the AI terminate in a tonotopic fashion

in the DNLL by forming progressively laterodorsally (lf) to

medioventrally (hf) located, somewhat curved fiber

arrangements. The corticolemniscal terminal fields mimic

the fibrodendritic orientation of horizontally and vertically

elongated cells, which we identified in our Golgi prepara-

tions. Electrophysiological mapping studies on the NLL in

the gerbil are lacking. In the cat DNLL, the low-to-high fre-

quency gradient of narrowly tuned auditory-responsive

neurons was initially described to run dorsoventrally (Ait-

kin et al., 1970). Subsequent tracing studies of colliculo-

lemniscal connections suggested a roughly similar but

rather laterodorsal-to-medioventrally oriented low-to-high

frequency organization based on the curved cell laminae

in the DNLL (Malmierca et al., 1996; Bajo et al., 1999).

This would correspond to the topography of corticolem-

niscal fibers in the gerbil. In rat, however, either no tono-

topy within the DNLL was found (Kelly et al., 1998a) or a

concentric pattern of hf units located at the outer mar-

gins and lf units located centrally within this nucleus was

suggested (Friauf, 1992; Caicedo and Herbert, 1993;

Merchan et al., 1994; Kelly et al., 1998b; Bajo et al.,

1998). Apparently, the question of the detailed functional

organization of the DNLL across species still remains

open.

Corticofugal terminations arising from the gerbil’s AI to

the INLL and VNLL do not show an obvious topographic

arrangement. Again, these nuclei have not yet been elec-

trophysiologically probed in the gerbil. In several other

species it has been suggested that the INLL and VNLL

are tonotopically organized but in a rather complex

mosaic fashion (for review and discussion, see Kelly

et al., 1998b; Malmierca and Merchan, 2004), which was

not evident in the distribution of corticolemniscal termi-

nations found in the gerbil.

There are indications that some mammalian cortico-oli-

vary (VNTB, LSO in rat: Feliciano et al., 1995) and cortico-

cochlear-nuclear projections (guinea pig: Jacomme et al.,

2003) are tonotopic, as seen by topographic shifts of

tracer injections in the auditory cortex and respective

shifts of labeled axons in the target structures. We could

not provide sufficient evidence for that in the gerbil, but

the frequency-matched projection patterns to the tono-

topic divisions of the MGB, IC, and NLL suggest that the

projections from the AI to the tonotopic subnuclei of the

SOC (i.e., the LSO, MSO, MNTB, and SPN; Ryan et al.,

1982; Sanes et al., 1989, 1990; Muller, 1990; Behrend

et al., 2002; Dehmel et al., 2002; Kopp-Scheinpflug et al.,

2008; Tolnai et al., 2008; Day and Semple, 2011) and CN

(i.e., the AVCN, PVCN, and DCN; Ryan et al., 1982;

Melzer, 1984; Muller, 1990; Hancock and Voigt, 2002)

might terminate in a tonotopic fashion.

Functional considerations of tonotopic andnon-tonotopic corticofugal connections

On the anatomical basis of their topographic termina-

tion patterns, tonotopic corticofugal projections of the AI

potentially serve to modulate and gate frequency-specific

information in its target structures. Although these pro-

jections are probably all of an excitatory nature (Feliciano

and Potashner, 1995; Saldana et al., 1996; Bartlett and

Smith, 1999), their effects on the neuronal activity of the

subcortical neurons include both facilitation and inhibi-

tion. Corticofugally evoked facilitation is predominantly

found in subcortical neurons, which match the BF of the

cortically activated neurons, whereas corticofugally

induced inhibition is mainly found in non-matched sub-

cortical neurons. A selective cortical inactivation usually

reduces the activity of subcortical frequency-matched

neurons and elevates the activity of the non-matched

neurons (for review, see He, 2003a; Nunez and Mal-

mierca, 2007; Suga, 2008; Malmierca and Ryugo, 2011;

Suga, 2012). Often, these and other changes of subcorti-

cal receptive field properties (e.g., minimum threshold,

width of frequency tuning curve, shift of tuning curve) are



organized in a center (excitatory)–surround (inhibitory)

way (Yan and Ehret, 2002; Suga and Ma, 2003; Yan et al.,

2005).

Based on their spatially overlapping termination pat-

terns, non-tonotopic projections of AI are suitable for an

integration of frequency information locally in the target

structures. Alternatively, they may not transmit the

detailed spectral information about an acoustic cue but

other information. This could be, for example, temporal

information useful for triggering subcortical oscillations

(He, 2003b) or behaviorally relevant (task-dependent)

cortical information (Gao and Suga, 2000; Scheich et al.,

2007) in order to filter the auditory information flow

through the ascending system (for review, see Suga,

2012). As shown in the present study, non-tonotopic cor-

ticofugal connections mainly terminate in non-lemniscal

auditory structures. These structures commonly also pro-

cess non-auditory information (for review, see Huffman

and Henson, 1990; Budinger et al., 2006); thus, the de-

scending information about an acoustic cue can also be

integrated with ascending information about other sen-

sory cues (Budinger and Scheich, 2009). In any case, cor-

ticofugal connections of the AI have been shown to affect

subcortical neurons of non-lemniscal and lemniscal audi-

tory structures in a different way. For example, in vivo in-

tracellular recordings in the MGB of guinea pigs revealed

that during electric stimulation of the primary auditory

cortex, neurons in the MGm hyperpolarize, which leads to

suppression of their auditory response and spontaneous

firing. In contrast, neurons in the MGv depolarize, leading

to facilitation of their auditory response and spontaneous

firing (Xiong et al., 2004; Yu et al., 2004).

In case of both the tonotopic and non-tonotopic

descending connections, their impact on corticofugal

control on MGB, IC, NLL, SOC, and CN neurons may be

different and may decrease with increasing distance from

the AI. This is indicated by the declining number of corti-

cothalamic, corticocollicular, corticolemniscal, cortico-

olivary, and cortico-cochlear-nuclear projections, as

documented in the present study as well as in studies on

other species (e.g., rat: Feliciano et al., 1995; mouse: Hof-

stetter and Ehret, 1992). In contrast, one might argue

that the earlier the corticofugal control can act on the

ascending auditory pathway, the more substantial this

influence can be.

Moreover, it is a common finding that corticofugal pro-

jections terminate exclusively (MGB, NLL) or, in case of

bilateral labeling, predominantly on the ipsilateral side

(see also, e.g., Feliciano et al., 1995; Weedman and

Ryugo, 1996a; Mulders and Robertson, 2000; Jacomme

et al., 2003; Coomes and Schofield, 2004; Schofield and

Coomes, 2005; Meltzer and Ryugo, 2006; present study).

This is consistent with the finding that an auditory cortex

stimulation elicits more excitation with a shorter latency

in the ipsilateral IC than in the contralateral IC (Torterolo

et al., 1998). It also suggests that the auditory corticofu-

gal pathway predominantly modulates the activity evoked

by the contralateral ear, and thus follows the main route

of the ascending auditory pathway (Nordeen et al., 1983).

A notable exception is the CN, where the stronger cor-

tico-cochlear-nuclear projections terminate on the ipsilat-

eral side, but the effects on inital sound processing in the

ipsi- and contralateral CN after focal electrical stimulation

of the auditory cortex are similar for both sides (mouse:

Luo et al., 2008; Liu et al., 2010).

So far, the phenomena of direct corticofugal modula-

tions are interpreted in favor of a selected neuronal repre-

sentation of selected frequencies (‘‘egocentric selection’’;

see Suga and Ma, 2003) and an increased spectral reso-

lution of sounds in order to improve the perception of be-

havioral significant and time-critical frequency compo-

nents of acoustic signals (Yan et al., 2005). Moreover, it

is speculated that the corticofugal facilitation of lemniscal

pathway neurons and inhibition of non-lemniscal neurons

may be related to a modality-specific gating of auditory

information at the subcortical level and thus may shift the

attention within the auditory modality and across sensory

modalities (Yu et al., 2004; Xiong et al., 2004; Suga,

2012). It was also shown that, for example, corticocollicu-

lar projections mediate the re-learning of altered sound

localization cues (Bajo et al., 2010).

Nevertheless, it still remains largely unclear how the

corticofugal system modulates activity in the normal

brain and how, in turn, neurons of the auditory cortex use

the corticofugally modulated subcortical signals. Studies

in the auditory and other sensory systems suggest that

such corticofugal feedback may synchronize the subcorti-

cal and cortical activity (Contreras and Steriade, 1996;

He, 2003b; Eyding et al., 2003; Cotillon-Williams and Ede-

line, 2004; Steriade, 2006) and may adjust the receptive

field sizes in the cortex (Eyding et al., 2003; Cudeiro and

Sillito, 2006; Sillito et al., 2006; Jafari et al., 2007; Ma

and Suga, 2009). In any case, these issues require much

more future research.

ACKNOWLEDGMENTS

We thank K. Gruss, A. Gurke, U. Kreher, and J. Stall-

mann for their excellent histological assistance. We are

grateful to Dr. W. Zuschratter for his technical support

during the confocal laser scanning as well as Dr. A. Hess

and M. Schildt for providing the ORIS data. We also thank

the two anonymous reviewers for their most helpful com-

ments on earlier versions of the manuscript.

Budinger et al.


CONFLICT OF INTEREST STATEMENT

There are no conflicts of interest.

ROLE OF AUTHORS

All authors had full access to all the data in the study

and take responsibility for the integrity of the data and

the accuracy of the data analysis. E.B. designed the study

and performed the tracing experiments. J.M. performed

the Golgi impregnations and M.B. the electrophysiological

experiments. E.B., J.M., M.B., and H.S. wrote the

manuscript.

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The subcortical auditory structures in the Mongolian gerbil: II. Frequency-related topography of the connections with cortical field AI