Biology subjects

Kandasamey, P.

Publications and source records attributed to Kandasamey, P..

3 recordsLinked to original sources

bioRxiv2026

Dissociable control of persistence and adaptive updating in reward-guided behavior

Adaptive behavior requires a balance between persistence and flexibility, whereas excessive persistence and impaired updating characterize several neuropsychiatric disorders. Touchscreen-based cognitive tasks provide a reverse-translational framework because closely related visual-discrimination and reversal paradigms are used to phenotype cognitive flexibility in rodents and humans. Here, we examined the role of the melanin-concentrating hormone (MCH) system using appetitive touchscreen extinction and reversal tasks. Blocking MCHR1 had little effect while an established reward contingency remained valid, but facilitated behavioral adaptation when reinforcement was withdrawn or reversed. These findings suggest that MCHR1 signaling promotes persistence of previously reinforced behavior. We then chemogenetically activated lateral hypothalamic MCH neurons. Activation produced no detectable change in extinction, but altered learning during reversal. Notably, behavioral differences were also evident during a subsequent reversal performed without chemogenetic activation: mice previously exposed to MCH-neuron activation learned the new contingency more rapidly, yet showed greater persistence after individual errors. Thus, MCHR1 blockade and MCH-neuron activation affect distinct components of behavioral updating rather than producing simple opposite effects. Together, these findings identify dissociable MCH-system contributions to reward-contingency updating in a behavioral framework directly relevant to cross-species neuropsychiatric research.

animal behavior and cognition↗

bioRxiv2026

Melanin-concentrating hormone signaling regulates persistence and updating of reward-guided actions

Flexible behavior requires persistence when a strategy remains effective and rapid updating when its consequences change. Melanin-concentrating hormone (MCH) neurons in the lateral hypothalamus regulate feeding, reward and memory, but their contribution to reward guided flexibility is unknown. Here, mice learned an action-outcome contingency in a T-maze and then adapted when the reward location switched. MCHR1 antagonism throughout learning did not measurably alter Initial Learning but reduced perseverative choices and accelerated behavioral adaptation after the contingency switched. Endogenous LH-MCH activity was strongest while contingencies were being established or revised, declined as performance stabilized, distinguished rewarded from unrewarded outcomes, and reflected current outcomes in the context of recent and accumulated experience. MCHR1 blockade altered prelimbic responses to successful outcomes in both phases and opposed their progressive weakening during Rule Switch. Together, these findings identify MCH signaling as a regulator of how strongly past reward continues to guide behavior when contingencies change and reveal accompanying changes in prefrontal processing of successful outcomes.

neuroscience↗

bioRxiv2026

Melanin-concentrating hormone signaling regulates prefrontal updating of learned avoidance

Adaptive avoidance depends on a delicate balance: animals must act rapidly when a cue predicts danger, but suppress the same action when the cue no longer has consequence. How MCH neuromodulatory signaling shapes this prefrontal updating process remains poorly understood. Here, we identify melanin-concentrating hormone receptor 1 (MCHR1) signaling as a regulator of active avoidance extinction. Pharmacological MCHR1 antagonism with SNAP-94847 left acquisition of two-way active avoidance intact, but promoted extinction once the tone was no longer followed by shock. This effect was reproduced by prelimbic mPFC-targeted SNAP infusion, indicating that prefrontal MCHR1 signaling contributes to the persistence of learned avoidance. Fiber photometry from CaMKII-positive mPFC neurons revealed that MCHR1 antagonism enhanced excitatory prefrontal activity during successful avoidance and altered trial-history-dependent mPFC activity during extinction, most prominently on avoidance trials that followed previous avoidance. These findings identify MCHR1 signaling as a regulator of adaptive avoidance updating and suggest that MCHR1 antagonism facilitates extinction by altering prefrontal processing of recent action history when a formerly protective response loses behavioral value. Significance StatementIn anxiety- and trauma-related disorders, avoidance can persist long after danger is gone, interfering with daily life. While avoidance is essential for survival, it can become harmful when it is no longer needed. We found that blocking brain receptors for melanin-concentrating hormone helps mice stop responding to outdated warning signals while preserving their ability to learn from danger. We identify the medial prefrontal cortex as a key brain region where this intervention changes activity during fear-guided behavior. This study highlights a potential therapeutic strategy for reducing excessive avoidance without compromising normal protective responses.

neuroscience↗