Enhancement of auditory fear conditioning after housing in a

complex environment is attenuated by prior treatment with amphetamine

Lisa A. Briand, Terry E. Robinson and Stephen Maren

Lisa A. Briand, Terry E. Robinson and Stephen Maren

BackgroundBackground

Living in a complex environment increases: cerebral volume Dendritic spine density and number LTP Resistance to neural insult Synaptic connectivity

Living in a complex environment increases: cerebral volume Dendritic spine density and number LTP Resistance to neural insult Synaptic connectivity

BackgroundBackground

Hippocampal-dependent learning tasks affected by complex housing Morris water maze Hebb-Williams Maze

Pavlovian fear conditioning in mice

Hippocampal-dependent learning tasks affected by complex housing Morris water maze Hebb-Williams Maze

Pavlovian fear conditioning in mice

BackgroundBackground

Traditionally, cued fear is thought to be purely amygdala dependent and contextual fear, hippocampal and amygdala dependent.

Recently, the ventral hippocampus has been implicated in auditory fear conditioning.

Traditionally, cued fear is thought to be purely amygdala dependent and contextual fear, hippocampal and amygdala dependent.

Recently, the ventral hippocampus has been implicated in auditory fear conditioning.

BackgroundBackground Psychostimulants

Increase dendritic branching and spine density Regions implicated in behavioral sensitization

Block dendritic changes induced by complex environment Those changes that may be responsible for

learning and memory

Psychostimulants Increase dendritic branching and spine

density Regions implicated in behavioral sensitization

Block dendritic changes induced by complex environment Those changes that may be responsible for

learning and memory

PsychostimulantsPsychostimulants

Amphetamine increases dopamine in the synaptic cleft by acting as a false substrate for DAT

Amphetamine increases dopamine in the synaptic cleft by acting as a false substrate for DAT

VTA NAc

DA

GABA

GABA

VTA interneuron

Amphetamine&

Cocaine

Nicotine

+

Opiates

-

Ethanol (?)

-

QuestionsQuestions

Does a complex environment modulate learning in a Pavlovian fear-conditioning paradigm?

Does prior treatment with amphetamine modulate environmental effects on learning?

Does a complex environment modulate learning in a Pavlovian fear-conditioning paradigm?

Does prior treatment with amphetamine modulate environmental effects on learning?

DetailsDetails Sprague Dawley rats ♂ Housed for 3 months in

Individual plastic hanging cages (isolated) 20 x 23 x 20 cm

Groups of 3 rectangular plastic cages (social) 20 x 43 x 20 cm

Groups of 12 stainless-steel monkey cages (complex) 61 x 61 x 72 cm

Sprague Dawley rats ♂ Housed for 3 months in

Individual plastic hanging cages (isolated) 20 x 23 x 20 cm

Groups of 3 rectangular plastic cages (social) 20 x 43 x 20 cm

Groups of 12 stainless-steel monkey cages (complex) 61 x 61 x 72 cm

General MethodsGeneral Methods

Animals housed for 3 months in respective environments then housed in social/standard cages during tests

Day1 - Fear conditioning paradigm

Day2 - Contextual test

Day3 - CS test (auditory cue)

Animals housed for 3 months in respective environments then housed in social/standard cages during tests

Day1 - Fear conditioning paradigm

Day2 - Contextual test

Day3 - CS test (auditory cue)

Experiment 1Experiment 1

4 Pairings of tone (CS) with shock (US) 30 sec; 80 dB; 2 kHz 2 sec; 1 mA

Measured freezing (CR)

No statistical differences

4 Pairings of tone (CS) with shock (US) 30 sec; 80 dB; 2 kHz 2 sec; 1 mA

Measured freezing (CR)

No statistical differences

Experiment 1Experiment 1 CS alone elicits long-

term fear memory 6 min of tone (Black line)

Complex group shows prolonged freezing response

Difference due to complex environment rather than social housing

CS alone elicits long-term fear memory 6 min of tone (Black line)

Complex group shows prolonged freezing response

Difference due to complex environment rather than social housing

Experiment 1Experiment 1

Context alone does not elicit significant differences

Trend toward significance

Complex group may freeze more to context at later time points

Context alone does not elicit significant differences

Trend toward significance

Complex group may freeze more to context at later time points

ConclusionsConclusions

Housing in a complex environment facilitated Pavlovian fear conditioning

Effect of environment on conditioned fear was much stronger for auditory fear than contextual fear

Housing in a complex environment facilitated Pavlovian fear conditioning

Effect of environment on conditioned fear was much stronger for auditory fear than contextual fear

DiscussionDiscussion

Inconsistent with previous studies in mice (Duffy et al. ’01; Tang et al. ’01) Found equal effects of enrichment on

contextual and auditory fear Used single pairing of shock and tone

Species difference or methodological

Inconsistent with previous studies in mice (Duffy et al. ’01; Tang et al. ’01) Found equal effects of enrichment on

contextual and auditory fear Used single pairing of shock and tone

Species difference or methodological

DiscussionDiscussion

The isolated and socially housed animals may use additional time in the conditioning context to consolidate contextual fear memory

Whereas complex-housed animals may exhibit a ceiling effect

The isolated and socially housed animals may use additional time in the conditioning context to consolidate contextual fear memory

Whereas complex-housed animals may exhibit a ceiling effect

DiscussionDiscussion

Environmental complexity could modify the ventral hippocampus in a way that allows for the enhancement of cued fear while having only a slight effect on contextual fear.

Environmental complexity could modify the ventral hippocampus in a way that allows for the enhancement of cued fear while having only a slight effect on contextual fear.

Experiment 2Experiment 2

Robust behavioral sensitization pretreatment

21 consecutive days of amphetamine 4.0 mg/kg with intermittent doses of 0.5

mg/kg to measure extent of psychomotor sensitization

Robust behavioral sensitization pretreatment

21 consecutive days of amphetamine 4.0 mg/kg with intermittent doses of 0.5

mg/kg to measure extent of psychomotor sensitization

Experiment 2Experiment 2

Significantly more locomotion on day 21 than day 1 in response to amphetamine dose of 0.5 mg/kg

No difference in saline group

Significantly more locomotion on day 21 than day 1 in response to amphetamine dose of 0.5 mg/kg

No difference in saline group

Experiment 2Experiment 2

Divided into complex and “standard” cages (groups of 3) for 3 months after amphetamine N=12 for Complex Saline N=12 for Complex Amphetamine N=12 for Social Saline N=12 for Social Amphetamine

Divided into complex and “standard” cages (groups of 3) for 3 months after amphetamine N=12 for Complex Saline N=12 for Complex Amphetamine N=12 for Social Saline N=12 for Social Amphetamine

Experiment 2Experiment 2

CS alone elicits long-term fear conditioning

Complex/Saline group shows more robust freezing than all other groups

CS alone elicits long-term fear conditioning

Complex/Saline group shows more robust freezing than all other groups

Experiment 2Experiment 2

Contextual freezing

No differences between groups

Contextual freezing

No differences between groups

Experiment 3Experiment 3

Animals were moved to social housing (groups of 3) during the fear conditioning and testing in experiments 1 & 2

Experiment 3 simply left the complex housed animals in the same cage during testing

Animals were moved to social housing (groups of 3) during the fear conditioning and testing in experiments 1 & 2

Experiment 3 simply left the complex housed animals in the same cage during testing

Experiment 3Experiment 3

CS alone elicits long-term fear memory

Complex/saline group still shows more robust freezing response

CS alone elicits long-term fear memory

Complex/saline group still shows more robust freezing response

Experiment 3Experiment 3

Contextual Freezing No difference

Contextual Freezing No difference

ConclusionConclusion

Amphetamine attenuates cued fear conditioning in animals housed in a complex environment

Amphetamine attenuates cued fear conditioning in animals housed in a complex environment

DiscussionDiscussion Some research has shown that prior

exposure to stimulants limits structural plasticity associated with living in complex environment

Possibly, exposure to amphetamine blocked effect of complex environment to facilitate fear learning by limiting structural plasticity associated with living in complex environment

Some research has shown that prior exposure to stimulants limits structural plasticity associated with living in complex environment

Possibly, exposure to amphetamine blocked effect of complex environment to facilitate fear learning by limiting structural plasticity associated with living in complex environment

DiscussionDiscussion

An experiment with low doses methamphetamine prior to exposure to a complex environment showed more cortical weight than those without AMP

Low doses of amphetamine also improve recovery from brain injury and in conjunction with speech therapy, greater recovery from aphasia

An experiment with low doses methamphetamine prior to exposure to a complex environment showed more cortical weight than those without AMP

Low doses of amphetamine also improve recovery from brain injury and in conjunction with speech therapy, greater recovery from aphasia

DiscussionDiscussion There are synaptic connections between the

nucleus accumbens and both amygdala (fear; emotions) and ventral hippocampus (stress; anxiety)

There are synaptic connections between the nucleus accumbens and both amygdala (fear; emotions) and ventral hippocampus (stress; anxiety)

DiscussionDiscussion Studies that show drugs of abuse limit

future experience-dependent plasticity implicate the nucleus accumbens & parietal cortex

Complex environment affects plasticity in nucleus accumbens, caudate-putamen, and hippocampus

Studies that show drugs of abuse limit future experience-dependent plasticity implicate the nucleus accumbens & parietal cortex

Complex environment affects plasticity in nucleus accumbens, caudate-putamen, and hippocampus

ConclusionsConclusions

Dendritic morphology in the hippocampus and the amygdala may also be altered by environmental enrichment and potentially modulated by drug exposure

Exposure to drugs of abuse may limit future experience dependent plasticity

Dendritic morphology in the hippocampus and the amygdala may also be altered by environmental enrichment and potentially modulated by drug exposure

Exposure to drugs of abuse may limit future experience dependent plasticity