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Abstract:
Anxiety disorders constitute a major disease and social burden
worldwide; however, many questions concerning the underlying molecular
mechanisms still remain open. Besides the involvement of the major
excitatory (glutamate) and inhibitory (gamma aminobutyric acid (GABA))
neurotransmitter circuits in anxiety disorders, the stress system has
been directly implicated in the pathophysiology of these complex mental
illnesses. The glucocorticoid receptor (GR) is the major receptor for
the stress hormone cortisol (corticosterone in rodents) and is widely
expressed in excitatory and inhibitory neurons, as well as in glial
cells. However, currently it is unknown which of these cell populations
mediate GR actions that eventually regulate fear-and anxiety-related
behaviors. In order to address this question, we generated mice lacking
the receptor specifically in forebrain glutamatergic or GABAergic
neurons by breeding GR flox/flox mice to Nex-Cre or Dlx5/6-Cre mice,
respectively. GR deletion specifically in glutamatergic, but not in
GABAergic, neurons induced hypothalamic-pituitary-adrenal axis
hyperactivity and reduced fear-and anxiety-related behavior. This was
paralleled by reduced GR-dependent electrophysiological responses in the
basolateral amygdala (BLA). Importantly, viral-mediated GR deletion
additionally showed that fear expression, but not anxiety, is regulated
by GRs in glutamatergic neurons of the BLA. This suggests that
pathological anxiety likely results from altered GR signaling in
glutamatergic circuits of several forebrain regions, while modulation of
fear-related behavior can largely be ascribed to GR signaling in
glutamatergic neurons of the BLA. Collectively, our results reveal a
major contribution of GRs in the brain's key excitatory, but not
inhibitory, neurotransmitter system in the regulation of fear and
anxiety behaviors, which is crucial to our understanding of the
molecular mechanisms underlying anxiety disorders.
