Thursday, April 3, 2025
4/3/2025
The Effect of Social Isolation on Inhibitory Modulation of Tactile Processing - PROJECT SUMMARY The constant flow of sensory information into the nervous system is fundamental for interaction with the world. The brain’s ability to flexibly adjust sensitivity to various sensory stimuli is context-dependent and can be shifted on acute or chronic time scales in different internal states. This change can be advantageous or maladaptive; prey animals like rodents may benefit from becoming hypersensitive to sensory cues, as in a mouse listening for evidence of a predator, but chronic shifts in sensory processing may become detrimental and overwhelming. Importantly, a chronic shift in internal state can impact tactile processing – for example, stress induced by social isolation has significant effects on several measures of affective behavior and can lead to aberrant increases in tactile sensitivity. However, the neural circuit mechanisms underlying this shift in responsivity to touch remain unknown. The cuneate nucleus of the brainstem (Cu) is responsible for conveying tactile information from the upper body to higher-order sensorimotor regions. Recent work in the Azim lab showed that local inhibitory networks envelop the Cu in a ‘shell’ and can act to reduce or amplify responses to tactile signals. These inhibitory networks are modulated by top-down pathways that can regulate the transmission of incoming information, likely as a means of attenuating disruptive feedback while facilitating salient signals. Preliminary experiments designed to identify the origins of these top-down modulatory projections revealed that the central amygdala (CeA) provides direct inputs to the Cu inhibitory shell (CeA-Cu). Due to its involvement in stress and isolation, the CeA has emerged as a compelling candidate region linking chronic social isolation to tactile hypersensitivity. Projections from CeA are almost exclusively inhibitory, leading to the possibility that they inhibit Cu shell neurons, thus, disinhibiting (i.e., amplifying) tactile feedback transmitted through the Cu. The overarching goals of this proposal are to investigate how this pathway influences sensory signals under normal and pathological conditions. The central hypotheses are that: a) top-down projections from the CeA disinhibit the transmission of touch information carried through the brainstem; and b) that these circuits are implicated in the aberrant increase in tactile sensitivity following social isolation. To test these ideas, CeA-Cu projections will be activated and silenced using optogenetic approaches in mice, and tactile sensitivity will be measured using three distinct tactile behavioral assays. These perturbations will then be performed in socially isolated mice to determine if optogenetic activation is sufficient to “rescue” normal tactile processing. Finally, fiber photometry will be employed to measure neural activity at each component of the pathway following social isolation and during optogenetic stimulation – CeA neurons, their targets in the Cu shell, and the cuneolemniscal neurons that receive tactile inputs and convey these signals to the thalamus. This research will lead to better understanding of how altered internal states affect somatosensation and provide insight into mechanistic causes of sensory processing disorders.
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