The hypothalamic-pituitary-adrenal (HPA) axis habituates to repeated stress exposure. r We studied hypothalamic corticotropin-releasing hormone (CRH) neurons that form the apex of the HPA axis in a mouse model of stress habituation using repeated restraint.r The intrinsic excitability of CRH neurons decreased after repeated stress in a time course that coincided with the development of HPA axis habituation.r This intrinsic excitability plasticity co-developed with an expansion of surface membrane area, which increased a passive electric load and dampened membrane depolarization in response to the influx of positive charge.r We report a novel structure-function relationship for intrinsic excitability plasticity as a neural correlate for HPA axis habituation.

The activation of the hypothalamic-pituitary-adrenal (HPA) axis relies on excitation of neuroendocrine neurons in the paraventricular nucleus of the hypothalamus (PVN) that secrete corticotrophin-releasing hormone (CRH). Afferent glutamate synapses onto these PVN-CRH neurons convey critical excitatory inputs during stress, and also undergo stress-induced plasticity, highlighting their roles in both stress activation and adaptation of the HPA axis. In the present study, using whole-cell patch clamp recordings from PVN-CRH neurons in brain slices from adult mice, we found that the amplitude of action potential-dependent spontaneous EPSCs (sEPSCs) was larger than that of action potential independent miniature EPSCs (mEPSCs), suggesting that action potentials at individual axons recruited multiquantal transmission onto the same postsynaptic neurons (i.e. synaptic multiplicity). The large, putative multiquantal sEPSCs had fast rise times similar to mEPSCs, and were abolished by replacing extracellular Ca with Sr , indicating Ca -dependent synchronous release of multiple vesicles. Application of a low affinity, fast dissociating competitive AMPA receptor antagonist γ-d-glutamylglycine revealed that synaptic multiplicity resulted from multivesicular release targeting a common population of postsynaptic receptors. High-frequency afferent stimulation facilitated synaptic multiplicity, effectively increasing the upper limit of the dynamic range of synaptic transmission. Finally, we found that chronic variable stress (CVS), a stress model known to cause basal HPA axis hyperactivity, increased sEPSCs frequency but paradoxically decreased synaptic multiplicity. These results suggest that the CVS-induced synaptic changes may elevate the baseline excitatory drive at the same time as limiting the capacity for potentiation, and may contribute to the basal HPA axis hyperactivity.

Preys use their memory - where they sensed a predatory threat and whether a safe shelter is nearby - to dynamically control their survival instinct to avoid harm and reach safety. However, it remains unknown which brain regions are involved, and how such top-down control of innate behaviour is implemented at the circuit level. Here, we show that the anterior hypothalamic nucleus (AHN) is best positioned to perform this task as an exclusive target of the hippocampus (HPC) within the medial hypothalamic defense system. Selective optogenetic stimulation and inhibition of hippocampal inputs to the AHN revealed that the HPC→AHN pathway not only mediates the contextual memory of predator threats but also controls the goal-directed escape by transmitting information about the surrounding environment. These results reveal a new mechanism for experience-dependent, top-down control of innate defensive behaviours.

Preys use their memory - where they sensed a predatory threat and whether a safe shelter is nearby - to dynamically control their survival instinct to avoid harm and reach safety. However, it remains unknown which brain regions are involved, and how such top-down control of innate behaviour is implemented at the circuit level. Here, using adult male mice, we show that the anterior hypothalamic nucleus (AHN) is best positioned to control this task as an exclusive target of the hippocampus (HPC) within the medial hypothalamic defense system. Selective optogenetic stimulation and inhibition of hippocampal inputs to the AHN revealed that the HPC→AHN pathway not only mediates the contextual memory of predator threats but also controls the goal-directed escape by transmitting information about the surrounding environment. These results reveal a new mechanism for experience-dependent, top-down control of innate defensive behaviours.

Following the loss of a sensory modality, such as deafness or blindness, crossmodal plasticity is commonly identified in regions of the cerebrum that normally process the deprived modality. It has been hypothesized that significant changes in the patterns of cortical afferent and efferent projections may underlie these functional crossmodal changes. However, studies of thalamocortical and corticocortical connections have refuted this hypothesis, instead revealing a profound resilience of cortical afferent projections following deafness and blindness. This report is the first study of cortical outputs following sensory deprivation, characterizing cortical projections to the superior colliculus in mature cats ( = 5, 3 female) with perinatal-onset deafness. The superior colliculus was exposed to a retrograde pathway tracer, and subsequently labeled cells throughout the cerebrum were identified and quantified. Overall, the percentage of cortical projections arising from auditory cortex was substantially increased, not decreased, in early-deaf cats compared with intact animals. Furthermore, the distribution of labeled cortical neurons was no longer localized to a particular cortical subregion of auditory cortex but dispersed across auditory cortical regions. Collectively, these results demonstrate that, although patterns of cortical afferents are stable following perinatal deafness, the patterns of cortical efferents to the superior colliculus are highly mutable. When a sense is lost, the remaining senses are functionally enhanced through compensatory crossmodal plasticity. In deafness, brain regions that normally process sound contribute to enhanced visual and somatosensory perception. We demonstrate that hearing loss alters connectivity between sensory cortex and the superior colliculus, a midbrain region that integrates sensory representations to guide orientation behavior. Contrasting expectation, the proportion of projections from auditory cortex increased in deaf animals compared with normal hearing, with a broad distribution across auditory fields. This is the first description of changes in cortical efferents following sensory loss and provides support for models predicting an inability to form a coherent, multisensory percept of the environment following periods of abnormal development.