Convergence and segregation of excitatory and inhibitory afferents in the paraventricular thalamic nucleus.

The paraventricular thalamic nucleus (PVT) integrates subcortical signals related to arousal, stress, addiction, and anxiety with top-down cortical influences. Increases or decreases in PVT activity exert profound, long-lasting effects on behavior related to motivation, addiction and homeostasis. Yet the sources of its subcortical excitatory and inhibitory afferents, their distribution within the PVT, and their integration with layer-specific cortical inputs remain unclear. Using transgenic male and female mice selective for GABAergic and glutamatergic neurons, or for different cortical layers we found that the input organization of PVT is unique among thalamic nuclei. PVT received subcortical GABAergic and glutamatergic inputs from multiple, distinct hypothalamic and brainstem regions. Most regions provided either excitatory or inhibitory afferents however subcortical inputs with dual components have also been found. Most of these subcortical inputs selectively targeted the core region of the PVT that contained large number of densely packed calretinin-positive (CR+) neurons. Cortical afferents to PVT displayed layer specific segregation. Layer 5 neurons of the medial prefrontal cortex preferentially innervated the CR+ core, whereas layer 6 input was more abundant in the transition zone between PVT and the mediodorsal nucleus. These findings demonstrate extensive convergence of excitatory and inhibitory inputs from diverse subcortical sources, selectively, in a sharply delineated CR+ core region of PVT which is also under strong top-down control from layer 5. This unique organization may explain why the CR+ PVT core serves as a critical bottleneck in the subcortex-cortex communication involved in affective behavior.Significance Statement The paraventricular thalamic nucleus (PVT) is a critical hub that integrates diverse neural signals controlling arousal, emotion, and motivation. This integration depends on which brain regions excite or inhibit PVT and whether these inputs converge or segregate. The present study reveals that the PVT receives distinct excitatory and inhibitory inputs from multiple subcortical and cortical regions. Most afferents converge in a sharply delineated core region of PVT. The work offers new insights into how structural organization of thalamus can explain its influence on behavior like stress adaptation, craving or affective behavior. These findings can lead to novel understanding of PVT's function and guide future research to study therapeutic strategies aimed at restoring balanced neural dynamics in neuropsychiatric disorders.