Transcript Enhancement of auditory fear conditioning after housing in a

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
Background
 Living in a complex environment
increases:
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cerebral volume
Dendritic spine density and number
LTP
Resistance to neural insult
Synaptic connectivity
Background
 Hippocampal-dependent learning tasks
affected by complex housing
 Morris water maze
 Hebb-Williams Maze
 Pavlovian fear conditioning in mice
Background
 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.
Background
 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
 Amphetamine increases dopamine in
the synaptic cleft by acting as a false
substrate for DAT
Ethanol (?)
Opiates
-
GABA
Amphetamine
&
Cocaine
VTA interneuron
+
Nicotine
DA
GABA
VTA
NAc
Questions
 Does a complex environment modulate
learning in a Pavlovian fear-conditioning
paradigm?
 Does prior treatment with amphetamine
modulate environmental effects on
learning?
Details
 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 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)
Experiment 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
Experiment 1
 CS alone elicits longterm fear memory
 6 min of tone (Black line)
 Complex group shows
prolonged freezing
response
 Difference due to
complex environment
rather than social
housing
Experiment 1
 Context alone does
not elicit significant
differences
 Trend toward
significance
 Complex group may
freeze more to
context at later time
points
Conclusions
 Housing in a complex environment
facilitated Pavlovian fear conditioning
 Effect of environment on conditioned
fear was much stronger for auditory fear
than contextual fear
Discussion
 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
Discussion
 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
Discussion
 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 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
Experiment 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
Experiment 2
 Divided into complex and “standard”
cages (groups of 3) for 3 months after
amphetamine
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N=12 for Complex Saline
N=12 for Complex Amphetamine
N=12 for Social Saline
N=12 for Social Amphetamine
Experiment 2
 CS alone elicits
long-term fear
conditioning
 Complex/Saline
group shows more
robust freezing than
all other groups
Experiment 2
 Contextual
freezing
 No differences
between groups
Experiment 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
Experiment 3
 CS alone elicits longterm fear memory
 Complex/saline group
still shows more robust
freezing response
Experiment 3
 Contextual Freezing
 No difference
Conclusion
 Amphetamine attenuates cued fear
conditioning in animals housed in a
complex environment
Discussion
 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
Discussion
 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
Discussion
 There are synaptic connections between the
nucleus accumbens and both amygdala (fear;
emotions) and ventral hippocampus (stress;
anxiety)
Discussion
 Studies that show drugs of abuse limit
future experience-dependent plasticity
implicate the nucleus accumbens &
parietal cortex
 Complex environment affects plasticity
in nucleus accumbens, caudateputamen, and hippocampus
Conclusions
 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