Circadian modulation of anxiety: a role for somatostatin in the amygdala.

Pharmacological evidence suggests that the neuropeptide somatostatin (SST) exerts anxiolytic action via the amygdala, but findings concerning the putative role of endogenous SST in the regulation of emotional responses are contradictory. We hypothesized that an endogenous regulation of SST expression over the course of the day may determine its function and tested both SST gene expression and the behavior of SST knock out (SST⁻/⁻) mice in different aversive tests in relation to circadian rhythm. In an open field and a light/dark avoidance test, SST⁻/⁻ mice showed significant hyperactivity and anxiety-like behavior during the second, but not during the first half of the active phase, failing to show the circadian modulation of behavior that was evident in their wild type littermates. Behavioral differences occurred independently of changes of intrinsically motivated activity in the home cage. A circadian regulation of SST mRNA and protein expression that was evident in the basolateral complex of the amygdala of wild type mice may provide a neuronal substrate for the observed behavior. However, fear memory towards auditory cue or the conditioning context displayed neither a time- nor genotype-dependent modulation. Together this indicates that SST, in a circadian manner and putatively via its regulation of expression in the amygdala, modulates behavior responding to mildly aversive conditions in mice.

Role of the neural cell adhesion molecule (NCAM) in amygdalo-hippocampal interactions and salience determination of contextual fear memory.

Evidence suggests that the neural cell adhesion molecule (NCAM) is an important molecular constituent of adaptive and maladaptive circuit (re-)organization in the central nervous system. Here, we further investigate its putative involvement in amygdala and hippocampus functions during context fear memory formation. Using laser capture microdissection and quantitative RT-PCR, we show high NCAM mRNA expression levels in the lateral and basolateral subnuclei of the amygdala, as well as their training intensity- and context-dependent regulation during fear memory consolidation. Moreover, we demonstrate that deficits of NCAM-/- mice in context fear memory can be overcome through contextual pre-exposure, i.e. by reducing the modulatory influence of the amygdala on this hippocampus-dependent memory. On the contrary, NCAM-/- mice failed to increase contextual fear memory after salient overtraining, although they adequately increased their response to auditory-cued fear stimuli. Finally, we demonstrate a reduction of amygdalo-hippocampal theta synchronization in NCAM-/- mice during fear memory retrieval. Together, these results suggest an involvement of NCAM-mediated cell recognition processes in information processing of the amygdalo-hippocampal system and in the amygdala-mediated modulation of context fear memory according to stimulus salience.

Identification of a neuropeptide S responsive circuitry shaping amygdala activity via the endopiriform nucleus.

Neuropeptide S (NPS) and its receptor are thought to define a set of specific brain circuits involved in fear and anxiety. Here we provide evidence for a novel, NPS-responsive circuit that shapes neural activity in the mouse basolateral amygdala (BLA) via the endopiriform nucleus (EPN). Using slice preparations, we demonstrate that NPS directly activates an inward current in 20% of EPN neurons and evokes an increase of glutamatergic excitation in this nucleus. Excitation of the EPN is responsible for a modulation of BLA activity through NPS, characterized by a general increase of GABAergic inhibition and enhancement of spike activity in a subset of BLA projection neurons. Finally, local injection of NPS to the EPN interferes with the expression of contextual, but not auditory cued fear memory. Together, these data suggest the existence of a specific NPS-responsive circuitry between EPN and BLA, likely involved in contextual aspects of fear memory.