Herpes Simplex Virus 1 (HSV-1)-Based Vectors - Viral Vector Approaches in Neurobiology and Brain Diseases - page 77

In order to elucidate the role of the AMPA (alpha-amino-3-
hydroxy-5-methyl-4-isoxazole-propionic acid) receptor (AMPAR)
in fear conditioning and, more generally, to study molecular, cel-
lular, and circuit changes that occur in the brain during learning,
Rumpel and colleagues [ 196 ] used amplicons expressing the
AMPA glutamate receptor subtype 1 (GluR1). This study showed
that fear conditioning drives AMPAR into the synapse of a fraction
of postsynaptic neurons in the basolateral amygdala. In treated ani-
mals, 10-20 % reduction in AMPAR synaptic incorporation in the
basolateral amygdala provoked an impairment of memories that
depend on this structure [ 196 ]. Also to investigate the molecular
basis of fear conditioning and other behavioral paradigms, several
groups have manipulated the function of cyclic adenosine mono-
phosphate (cAMP) response element-binding protein (CREB),
using amplicons encoding the wild-type or a dominant-negative
form of this protein (CREB S133A ). In this way, it was shown that
changes in CREB function could infl uence the probability of indi-
vidual lateral amygdala neurons to be recruited into a fear memory
trace, suggesting a competitive model underlying memory forma-
tion, in which eligible neurons are selected to participate in a mem-
ory trace as a function of their relative CREB activity at learning.
Furthermore, Han et al. [ 197 , 198 ] have shown that increasing
CREB in the auditory thalamus enhances memory and generaliza-
tion of auditory conditioned fear, implicating that CREB-mediated
plasticity in the thalamus plays a role in this cognitive process.
Other study used the same vectors to demonstrate that hippocam-
pal overexpression of a dominant-negative form of CREB can
block long-term though not short-term memory for a socially
transmitted food preference, therefore involving hippocampal
CREB function in this type of memory [ 199 ]. This team has later
shown that, in a task where rats were trained to make a consistent
turning response in a water version of the cross maze, long-term
memory of a response strategy requires CREB function in the dor-
solateral striatum and is independent of CREB function in the dor-
sal hippocampus [ 200 ]. Using a model of protracted social isolation
in adult rats, Barrot et al. [ 201 ] observed an increase in anxiety-like
behavior and defi cits in both the latency of the onset of sexual
behavior and the latency to ejaculate. Using transgenic cAMP
response element (CRE)-LacZ reporter mice, the authors showed
that protracted social isolation also reduced CRE-dependent tran-
scription within the nucleus accumbens (NAc). This decrease in
CRE-dependent transcription was mimicked in nonisolated ani-
mals by local amplicon-based gene transfer of the dominant nega-
tive mutant of CREB. This study suggests a role for the NAc in
anxiety responses and in specifi c aspects of sexual behavior and
provides novel insight into the molecular mechanisms by which
social interactions affect brain plasticity and behavior [ 201 ].