Biology subjects

Sharpe, M.

Publications and source records attributed to Sharpe, M..

4 recordsLinked to original sources

bioRxiv2025

Calbindin Stratifies Midbrain Dopaminergic Neurons Governing Distinct Aspects of Locomotion

Despite advances in delineating the molecular diversity and projection patterns of midbrain dopaminergic (DA) neurons, their specific contributions to locomotion and motor learning remain poorly defined. Here, we applied intersectional ablation and chemogenetic approaches to dissect the distinct roles of calbindin-expressing (CALB1+) and non-expressing (CALB1-) DA neurons in locomotion. Using newly engineered intersectional constructs, we ablated CALB1+ or CALB1- DA neurons in the mouse midbrain. Loss of either subtype led to pronounced deficits in the initiation and vigor of voluntary movements, as demonstrated by a reduction in peak speed, acceleration and deceleration of locomotor bouts. Notably, only CALB1- ablation disrupted locomotor learning. Beyond these functional effects, we observed that selective ablation of CALB1 DA neurons induced local microglial activation and was followed by a non-cell-autonomous loss of CALB1- DA neurons, suggesting that CALB1- neurons are more vulnerable to inflammation triggered by CALB1 neuron loss. We then confirmed these findings by performing acute inhibition of either population using inhibitory DREADD hM4Di. CALB1- DA neurons inhibition impaired the initial acquisition of locomotor learning, whereas inhibition of CALB1+ DA neurons disrupted the retention of acquired motor skills from previous days. Moreover, inhibition of CALB1+ DA neurons further impaired the initiation and amplitude of voluntary movements, as well as the velocity and acceleration/deceleration of locomotor bouts. Together, these findings provide causal evidence for functional specialization among molecularly distinct midbrain DA subtypes and reveal new aspects of mesostriatal circuit organization underlying locomotion and motor memory.

neuroscience↗

bioRxiv2024

A common stay-on-goal mechanism in anterior cingulate cortex for information and effort choices

Humans and non-humans alike often make choices to gain information, even when the information cannot be used to change the outcome. Prior research has shown the anterior cingulate cortex (ACC) is important for evaluating options involving reward-predictive information. Here we studied the role of ACC in information choices using optical inhibition to evaluate the contribution of this region during specific epochs of decision making. Rats could choose between an uninformative option followed by a cue that predicted reward 50% of the time vs. a fully informative option that signaled outcomes with certainty, but was rewarded only 20% of the time. Reward seeking during the informative S+ cue decreased following ACC inhibition, indicating a causal contribution of this region in supporting reward expectation to a cue signaling reward with certainty. Separately in a positive control experiment and in support of a known role for this region in sustaining high-effort behavior for preferred rewards, we observed reduced lever presses and lower breakpoints in effort choices following ACC inhibition. The lack of changes in reward latencies in both types of decisions indicate the motivational value of rewards remained intact, revealing instead a common role for ACC in maintaining persistence toward certain and valuable rewards. Graphical Summary O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=59 SRC="FIGDIR/small/619920v2_ufig1.gif" ALT="Figure 1"> View larger version (11K): org.highwire.dtl.DTLVardef@6fa3b2org.highwire.dtl.DTLVardef@1642fa8org.highwire.dtl.DTLVardef@74d4d9org.highwire.dtl.DTLVardef@421297_HPS_FORMAT_FIGEXP M_FIG C_FIG Significance StatementWe often make choices to gain information, even when the information cannot be used to change the outcome. Here we investigated the precise timing of the role of the anterior cingulate cortex (ACC) in decisions that involve seeking certain versus uncertain rewards. By optically inhibiting ACC neurons, we demonstrate that this region is crucial for maintaining persistence toward rewards signaled with certainty, without altering the motivational value of the reward itself. In a positive control experiment, we also confirm that ACC is important in effort-based choice. The findings reveal a common role for ACC in maintaining persistence toward certain and valuable rewards, necessary for making optimal decisions. These results have implications for understanding psychiatric disorders involving maladaptive reward-seeking behavior.

neuroscience↗

bioRxiv2024

Prior cocaine use diminishes encoding of latent information by orbitofrontal, but not medial, prefrontal ensembles

Maladaptive decision-making is a hallmark of substance use disorders, though how drugs of abuse alter neural representations supporting adaptive behavior remains poorly understood. Past studies show the orbitofrontal (OFC) and prelimbic (PL) cortices are important for decision making, tracking both task-relevant and latent information. However, previous studies have focused on how drugs of abuse impact the firing rates of individual units. More work at the ensemble level is necessary to accurately characterize potential drug-induced changes. Using single-unit recordings in rats during a multidimensional decision-making task and then applying population and ensemble level analyses, we show that prior use of cocaine altered the strength and structure of task-relevant and latent representations in the OFC, changes relatable to suboptimal decision making in this and perhaps other settings. These data expand our understanding of the neuropathological underpinnings of maladaptive decision-making in SUDs, potentially enabling enhanced future treatment strategies.

neuroscience↗

bioRxiv2020

Devaluation-sensitive responding to preconditioned cues requires orbitofrontal cortex during initial cue-cue learning

The orbitofrontal cortex (OFC) is necessary for value inference in tests of model-based reasoning. This ability could be accounted for by either representation of value or by representation of broader associative structure. Our lab recently reported correlates of both value and of valueless associative structure in OFC using single-unit recording (Sadacca et al., 2018). This incidental stimulus-stimulus representation was surprising since OFC was thought to be involved only when items of biological significance were driving responses. However, we did not assess whether this activity was necessary for encoding the associative information that would contribute to value inference during probe testing. Here, we used optogenetic OFC inhibition during sensory preconditioning to test this. We found that OFC inhibition during preconditioning impaired value inference during the probe test, demonstrating that the correlates we previously observed are not simply downstream readouts of sensory processing and instead contribute to encoding valueless sensory associative information.

neuroscience↗