Hippocampal-hypothalamic circuit controls context-dependent innate defensive responses

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 behavior 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 behaviors

Kainate Receptor-mediated Regulation of Chloride Homeostasis

A balance between excitatory and inhibitory activity is needed to maintain proper brain function. At inhibitory synapses, potassium-chloride cotransporter 2 (KCC2) has long been known to be a critical regulator of inhibition through its ability to maintain a low intracellular chloride level. Surprisingly, KCC2 has recently been found to play an important role at the excitatory synapse, where it interacts with several proteins involved in excitatory neurotransmission, including the kainate receptor subunit GluK2. It is known that independent of kainate receptor activation, the physical interaction between KCC2 and GluK2 is important for KCC2 surface expression, oligomerization and recycling. However, it is unknown whether the activity of kainate receptors can directly influence KCC2 function. My thesis research has revealed a novel functional role for kainate receptors in CA3 pyramidal cells. I show that activating KARs in the hippocampus hyperpolarizes EGABA and increases the driving force for Cl-. This hyperpolarization occurs through both ionotropic and metabotropic KAR signaling. The metabotropic signaling mechanism is dependent on KCC2, but the ionotropic signaling mechanism produces a hyperpolarization of EGABA even in the absence of KCC2 transporter function. These results demonstrate a novel functional interaction between a glutamate receptor and KCC2, a transporter critical for maintaining inhibition, suggesting that the KAR: KCC2 interaction may play an important role in excitatory: inhibitory (E:I) balance in the hippocampus. Additionally, the ability of KARs to regulate chloride homeostasis independently of KCC2 suggests that KAR signaling can regulate inhibition in multiple ways that may involve other chloride transporters. Activation of kainate-type glutamate receptors could serve as an important mechanism for increasing the strength of inhibition during period of strong glutamatergic activity and a potential target for developing strategies to treat diseases characterized by an imbalance in excitation and inhibition.Ph.D