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Subthalamic nucleus (STN) is the main source of feed-forward excitation in the basal ganglia and a main target of therapeutic deep brain stimulation in movement disorders. Alleviation of motor symptoms during STN stimulation can be accompanied by deterioration of abilities to quickly choose between conflicting alternatives. Cortical afferents to the subthalamic region (ST), comprising STN and zona incerta (ZI), include projections from the medial prefrontal cortex (mPFC), yet little is known about prefrontal-subthalamic coordination and its relevance for decision-making. Here we combined electrophysiological recordings with optogenetic manipulations of projections from mPFC to ST in mice as they performed a spatial working memory task (T-maze) or explored an elevated plus maze (anxiety test). We found that gamma oscillations (30–70 Hz) are coordinated between mPFC and ST at theta (5–10 Hz) and, less efficiently, at sub-theta (2–5 Hz) frequencies. An optogenetic detuning of the theta/gamma cross-frequency coupling between the regions into sub-theta range impaired performance in the T-maze, yet did not affect anxiety-related behaviors in the elevated plus maze. Both detuning and inhibition of the mPFC-ST pathway led to repeated incorrect choices in the T-maze. These effects were not associated with changes of anxiety and motor activity measures. Our findings suggest that action selection in a cognitively demanding task crucially involves theta rhythmic coordination of gamma oscillatory signaling in the prefrontal-subthalamic pathway., This work was supported by the Deutsche Forschungsgemeinschaft (DFG: SPP1665, PO1799/1–2, Heisenberg Program, PO1799/2–1 and PO1799/3-1, AP).

Reduced food intake is common to many pathological conditions, such as infection and toxin exposure. However, cortical circuits that mediate feeding responses to these threats are less investigated. The anterior insular cortex (aIC) is a core region that integrates interoceptive states and emotional awareness and consequently guides behavioral responses. Here, we demonstrate that the right-side aIC CamKII+ (aICCamKII) neurons in mice are activated by aversive visceral signals. Hyperactivation of the right-side aICCamKII neurons attenuates food consumption, while inhibition of these neurons increases feeding and reverses aversive stimuli-induced anorexia and weight loss. Similar manipulation at the left-side aIC does not cause significant behavioral changes. Furthermore, virus tracing reveals that aICCamKII neurons project directly to the vGluT2+ neurons in the lateral hypothalamus (LH), and the right-side aICCamKII-to-LH pathway mediates feeding suppression. Our studies uncover a circuit from the cortex to the hypothalamus that senses aversive visceral signals and controls feeding behavior., Food intake can be attenuated by visceral aversive stimuli in pathological conditions. Here the authors identify a unilateral neural circuit from the CamKII-positive neurons in the anterior insular cortex to the vGluT2-positive neurons in the lateral hypothalamus that controls feeding responses to visceral aversive stimuli.

NMDA receptors (NMDARs) are crucial for excitatory synaptic transmission and synaptic plasticity. The number and subunit composition of synaptic NMDARs are tightly controlled by neuronal activity and sensory experience, but the molecular mechanism mediating NMDAR trafficking remains poorly understood. Here, we report that RIM1, with a well-established role in presynaptic vesicle release, also localizes postsynaptically in the mouse hippocampus. Postsynaptic RIM1 in hippocampal CA1 region is required for basal NMDAR-, but not AMPA receptor (AMPAR)-, mediated synaptic responses, and contributes to synaptic plasticity and hippocampus-dependent memory. Moreover, RIM1 levels in hippocampal neurons influence both the constitutive and regulated NMDAR trafficking, without affecting constitutive AMPAR trafficking. We further demonstrate that RIM1 binds to Rab11 via its N terminus, and knockdown of RIM1 impairs membrane insertion of Rab11-positive recycling endosomes containing NMDARs. Together, these results identify a RIM1-dependent mechanism critical for modulating synaptic function by facilitating membrane delivery of recycling NMDARs., Rab3-interacting molecules (RIMs) are a key component of the presynaptic active zone that regulate neurotransmitter release. Here, the authors show that RIM1 also has postsynaptic function to organize NMDA receptors and synaptic response.

N-methyl-D-aspartate (NMDA) receptor overactivation is involved in neuronal damage after stroke. However, the mechanism underlying NMDA receptor-mediated excitotoxicity remains unclear. In this study, we confirmed that excessive activation of NMDARs led to cell apoptosis in PC12 cells and in primary cultured cortical neurons, which was mediated predominantly by the GluN2B-containing, but not the GluN2A-containing NMDARs. In addition, Clathrin-dependent endocytosis participated in NMDA-induced excitotoxicity. Furthermore, we identified that GluN2B-containing NMDARs underwent endocytosis during excessive NMDA treatment. Peptides specifically disrupting the interaction between GluN2B and AP-2 complex not only blocked endocytosis of GluN2B induced by NMDA treatment but also abolished NMDA-induced excitotoxicity. These results demonstrate that Clathrin-dependent endocytosis of GluN2B-containing NMDARs is critical to NMDA-induced excitotoxicity in PC12 cells and in primary cultured cortical neurons, and therefore provide a novel target for blocking NMDAR-mediated excitotoxicity.