Keywords
basal amygdala; nucleus accumbens; social aversion and social reward;
c-Fos; calcium activity
Introduction
Accurate detection of and adaptive responding to emotionally salient
stimuli are vital brain functions; this applies to both rewarding
stimuli that elicit appetitive and consummatory behaviors and aversive
stimuli that elicit defensive avoidance and escape behaviors.
Pathologies of emotional stimulus processing constitute major symptoms
in various neuropsychiatric disorders, including major depressive
disorder, schizophrenia, and social anxiety disorder. The amygdala is a
major region in the neural circuitries of both aversion and reward
processing . The lateral amygdala (LA) and basal/basolateral amygdala
(BA) are cortex-like, comprising primarily pyramidal glutamatergic
neurons . Glutamate neurons in LA receive and integrate inputs from
thalamic and cortical sensory neurons encoding innate and conditioned
stimuli , and are the major afferents onto BA glutamate neurons . The
function(s) of BA glutamate neurons is less well understood: they
project to several sub-cortical and cortical regions, including nucleus
accumbens (NAc) core and shell, which are also major regions of reward
and aversion processing .
In mice, a small number of studies of amygdala processing of stimulus
valence (reward and aversion) have included the amygdala-to-NAc neural
pathway. In a study of LA/BA-NAc neurons, mice acquired operant behavior
for optogenetic self-stimulation of LA/BA-NAc somata, consistent with
reward encoding . LA/BA-NAc neuronal density was highest in the
anteroposterior (AP) intermediate LA/BA , where the BA comprises both
medial anterior/magnocellular and lateral posterior/parvocellular
sub-regions . Using retrograde tracing and in vivo single-cell
electrophysiological recording to measure responsiveness of LA/BA-NAc
neurons to sucrose reward (S) or quinine aversion (Q), 16% were excited
by S, 3% by Q and 3% by S and Q (16% were inhibited by S, 13% by Q
and 5% by S and Q) . Using putative marker genes for neurons
responsive, in terms of immediate-early gene Fos expression, to
either reward (female) or aversion (foot shock), 70% of BA-NAc neurons
expressed the putative reward-neuron gene Ppp1r1b (protein
phosphatase 1, regulatory inhibitor subunit 1b) and were
posterior/parvocellular, and 30% expressed the putative aversion-neuron
gene Rspo2 (R-spondin 2) and were intermediate/magnocellular.
Optogenetic activation of Rspo2 + BA-NAc neurons
resulted in contextual aversion conditioning . AnteriorRspo2 + BA-NAc neurons are reported to also
express Fezf2 (FEZ family zinc finger 2), and to respond to
aversion (air puff, tail shock) and not to reward (sucrose), as assessed
using calcium-sensor fibre photometry .
One feature of BA-NAc neuron research to-date, as exemplified by the
above studies, has been the focus on physical emotional stimuli. In male
mice, estrous female was applied as a social reward stimulus (SR) in a
single study , and aggressive-dominant male as social aversion stimulus
(SA) remains to be applied. Given the particularly high emotional
salience of social stimuli , and the common application of
aggressive-dominant male as a chronic stressor , a study directly
comparing engagement of BA-NAc neurons by estrous-receptive female and
aggressive-dominant male would be informative. The iterative aims of the
current study were to: (1) Establish the AP distribution of
retrogradely-labelled BA-NAc (core and shell) neuronal somata activated
in terms of c-Fos by SR and/or SA. (2) Using targeted recombination in
active populations (TRAP) in an AP subregion with a relatively high
density of SR and SA BA-NAc neurons, determine whether they are
monovalent or dual-valent. (3) Having identified the engagement of
BA-NAc neurons by SR (or SA) using ex vivo methods, apply bulk
calcium-sensor fibre photometry to provide in vivo evidence for
engagement of BA-NAc neurons during either distal or proximal
interactions with SR. Aim 1 demonstrated that AP-intermediate BA was
relatively rich in BA-NAc neurons responsive to SR and/or SA, and
AP-posterior BA was also rich in BA-NAc neurons responsive to SA. Aim 2
demonstrated that substantial and equable proportions of intermediate
BA-NAc neurons were monovalent with respect to SR and SA. Aim 3
demonstrated that intermediate BA-NAc neurons were engaged during distal
and proximal interactions with SR. These findings further understanding
of the anatomical organization and valence specificity of BA-NAc neurons
engaged in the processing of social stimuli of high emotional
significance; they are relevant to both adaptive socio-emotional
processing and the pathologies thereof that are common in stress-related
neuropsychiatric disorders.