Biology subjects

Picciotto, M. R.

Publications and source records attributed to Picciotto, M. R..

7 recordsLinked to original sources

bioRxiv2026

Social Novelty Recruits a Dysfunctional Nucleus Accumbens Ensemble That Drives Social Avoidance in a Shank3-/- Autism Model

Social behavior deficits are a common symptom of neuropsychiatric disorders, including autism spectrum disorder (ASD), but there are limited pharmacological treatments for these symptoms. Understanding how neurons encode social information will give insight into identifying novel pharmacological targets to address this unmet need. SHANK3 encodes a postsynaptic scaffold protein and is a common risk gene for several neuropsychiatric disorders characterized by social deficits, including ASD. Our lab previously developed the Shank3{Delta}e4-22 mouse model, which shows a loss of social preference and altered connectivity in the nucleus accumbens (NAc), a critical region for social behaviors. However, it remains unknown how Shank3 deletion alters the encoding of social cues in the NAc. To address this gap in knowledge, we characterized the function of neurons activated by social interaction, or social ensembles, in WT and Shank3{Delta}e4-22 mice using a combination of genetic capture techniques, chemogenetics, optogenetics, and one-photon calcium imaging. We show that NAc social ensembles of WTs and Shank3{Delta}e4-22 mice drive opposing social behaviors: while NAc social ensembles encode appetitive social cues in WT mice, they encode avoidance in Shank3{Delta}e4-22 mice. We further find that, in Shank3{Delta}e4-22 mice, NAc neurons are hyperactive and have hypermodulatory responses to social novelty. Suppressing the activity of social ensembles during social novelty prevents future social avoidance and restores social investigation in Shank3{Delta}e4-22 mice. Taken together, our data show that Shank3{Delta}e4-22 mice have an enhanced NAc response to social novelty that actively drives social aversion, rather than a loss of social motivation.

neuroscience↗

bioRxiv2026

mPFC Synaptosome Proteomics Reveals Novel Pathways and Muscarinic Receptor Changes in a Learned Helplessness Mouse Model

Stressful events are a leading factor in development of depression. The medial prefrontal cortex (mPFC) is strongly associated with depression etiology and exposure to uncontrollable stressors results in synaptic dysfunction and loss. Learned helplessness is a behavioral paradigm that measures effects of repeated exposure to uncontrollable, inescapable stress on later responses to escapable stress. We therefore performed a proteomic analysis of mPFC synaptosomes in a mouse learned helplessness model to identify molecular changes that could contribute to functional consequences of inescapable stress. Male and female mice were evaluated at baseline and following exposure to escapable or inescapable stress followed by an active avoidance test. Label-free mass spectrometry followed by pathway and protein-protein interaction network analyses identified alterations in signaling pathways involved in energy metabolism, neurotransmitter signaling, and protein shuttling. Furthermore, phosphoproteomics revealed alterations related to synaptic function, neurotransmitter signaling and protein internalization, as well as changes in activity of kinases previously identified as mediators of antidepressant efficacy (GSK3B) and receptor internalization (ADRBK1). We more deeply examined alterations in the Acetylcholine Receptor Signaling Pathway, and identified muscarinic receptor proteins (Chrm1, Chrm2, Chrm4) and key proteins involved in their translocation to and from the membrane. These results identify substantial changes in the mPFC proteome following exposure to inescapable stressors. In addition, mPFC muscarinic cholinergic signaling is well placed to mediate responses to an inescapable stressor. This proteomic study will be useful in guiding studies of human mPFC relevant to depression. Data are available via ProteomeXchange with identifier PXD073765.

neuroscience↗

bioRxiv2025

Noradrenergic inputs to the basolateral amygdala have bidirectional effects on coping behavior and neuronal activity in mice

Norepinephrine (NE) signaling is disrupted in stress disorders, with insufficient NE signaling implicated in major depressive disorder and hyperactive NE signaling associated with post-traumatic stress disorder, suggesting that adequate mood regulation requires optimal NE levels. The basolateral amygdala (BLA) is a hub for stress processing and receives dense noradrenergic innervation from the locus coeruleus (LC), the primary noradrenergic nucleus in the brain. The relationship between LC activity and cognitive/behavioral function during fear conditioning has been described as an inverted U, in which moderate LC activity, and subsequent NE release, is required for adaptive coping to threats, while hyperactive LC-NE signaling drives maladaptive behavioral responses. We used fiber photometry to measure NE signaling in the mouse BLA during acute behavioral responses to escapable and inescapable stressors, and then used an optogenetic approach to stimulate the noradrenergic terminals in the BLA at different frequencies to evaluate effects on coping behavior and cFos expression in the LC-BLA circuit. We found that low-frequency stimulation of the circuit inhibited both passive coping and BLA neuronal activity, while high-frequency stimulation had the opposite effect; the behavioral effects were not mediated by sex, but the cFos effects were specific to males. This study represents an expansion of the inverted U framework to encompass LC-BLA signaling driving acute behavioral responses to stress. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=79 SRC="FIGDIR/small/677150v1_ufig1.gif" ALT="Figure 1"> View larger version (23K): org.highwire.dtl.DTLVardef@1b642a7org.highwire.dtl.DTLVardef@d20eedorg.highwire.dtl.DTLVardef@d22aa7org.highwire.dtl.DTLVardef@1ee4291_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIBLA NE levels signal behavioral transitions between coping responses to stress C_LIO_LILow-frequency stimulation of BLA NE terminals inhibits passive coping and BLA cFos C_LIO_LIHigh-frequency stimulation of BLA NE terminals promotes passive coping and BLA cFos C_LIO_LIBehavioral effects are similar across sexes, but cFos alterations are male- specific C_LI

neuroscience↗

bioRxiv2025

An Anterior Cingulate Cortex Neuronal Ensemble Controls Contextual Opioid Analgesic Tolerance

Opioids are first-line treatments for pain; however, tolerance leads to decreased efficacy and escalated dosing, increasing the risk of opioid use disorder and overdose. Despite well-established cellular and molecular adaptations, opioid analgesic tolerance can be rapidly reversed in settings where these drugs are not expected. The specific neuronal populations that orchestrate this expectation-based tolerance are not known. In this study, we used a contextual tolerance training method, whole-brain clearing, and immunostaining to identify brain regions involved in contextual tolerance and to pinpoint a neuronal ensemble in the anterior cingulate cortex (ACC) that is activated by contextual analgesic tolerance. We observed that calcium activity in principal neurons of the ACC is suppressed by fentanyl in opioid-naive mice and during contextual reversal, but not during contextual tolerance. Chemogenetic silencing of the ACC induced analgesic tolerance reversal in the opioid-associated context without affecting thermal nociception in opioid-free mice. Conversely, chemogenetic activation of the ACC contextual tolerance-active neuronal ensemble triggered analgesic tolerance in an unassociated context. This research highlights the role of ACC neuronal ensembles in mediating expectation-driven, contextual opioid analgesic tolerance without affecting basal nociception. Modulating ACC activity could provide a promising strategy to improve pain relief while maintaining the essential ability to detect harmful stimuli.

neuroscience↗

bioRxiv2024

Molecular Specification of Claustro-Amygdalar and Paleocortical Neurons and Connectivity

The ventropallial excitatory neurons (ExNs) in the claustro-amygdalar complex and piriform cortex (PIR; part of paleocortex) form crucial reciprocal connections with the prefrontal cortex (PFC), integrating cognitive and sensory information that result in adaptive behaviors. Early-life disruptions in these circuits are linked to neuropsychiatric disorders, highlighting the importance of understanding their development. Our study uncovers that transcription factors SOX4, SOX11, and TFAP2D play a pivotal role in the development, identity, and PFC connectivity of these neurons. Using mouse models, we demonstrate that the absence of transcription factors SOX4 and SOX11 in post-mitotic ExNs dramatically reduces the size of the basolateral amygdala complex (BLC), claustrum, and PIR. SOX4 and SOX11 control BLC formation through direct regulation of Tfap2d expression. Cross-species analyses, including humans, identified conserved Tfap2d expression in developing ExNs of BLC, claustrum, paleocortex including PIR, and the associated transitional areas of the frontal, insular and temporal cortex. While the loss and haploinsufficiency of Tfap2d yield similar alterations in learned threat behaviors, differences emerge in the manifestation of Tfap2d dosage, particularly in terms of changes observed in BLC size and the connectivity pattern between the BLC and PFC. This underscores the significance of Tfap2d dosage in orchestrating developmental shifts in BLC-PFC connectivity and behavioral modifications reminiscent of symptoms of neuropsychiatric disorders. Together, these findings reveal key elements of a conserved gene regulatory network that shapes the development and function of crucial ventropallial ExNs and their PFC connectivity and offer insights into their evolution and alterations in neuropsychiatric disorders.

neuroscience↗

bioRxiv2023

Acetylcholine signaling in the medial prefrontal cortex mediates the ability to learn an active avoidance response following learned helplessness training

Increased brain levels of acetylcholine (ACh) are observed in subsets of patients with depression and increasing ACh levels chronically can precipitate stress-related behaviors in humans and animals. Conversely, optimal ACh levels are required for cognition and memory. We hypothesize that ACh signaling is important for encoding both appetitive and stress-relevant memories, but that excessive increases in ACh result in a negative encoding bias in which memory formation of a stressful event is aberrantly strengthened, potentially contributing to the excessive focus on negative experience that could lead to depressive symptoms. The medial prefrontal cortex (mPFC) is critical to control the limbic system to filter exteroceptive cues and stress-related circuits. We therefore evaluated the role of ACh signaling in the mPFC in a learned helplessness task in which mice were exposed to repeated inescapable stressors followed by an active avoidance task. Using fiber photometry with a genetically-encoded ACh sensor, we found that ACh levels in the mPFC during exposure to inescapable stressors were positively correlated with later escape deficits in an active avoidance test in males, but not females. Consistent with these measurements, we found that both pharmacologically- and chemogenetically-induced increases in mPFC ACh levels resulted in escape deficits in both male and female mice, whereas chemogenetic inhibition of ACh neurons projecting to the mPFC improved escape performance in males, but impaired escape performance in females. These results highlight the adaptive role of ACh release in stress response, but also support the idea that sustained elevated ACh levels contribute to maladaptive behaviors. Furthermore, mPFC ACh signaling may contribute to depressive symptomology differentially in males and females.

neuroscience↗

bioRxiv2019

Cumulative effects of social stress on reward-guided actions and prefrontal cortical activity

When exposed to chronic social stress, animals display behavioral changes that are relevant to depressive-like phenotypes. However, the cascading relationship between incremental stress exposure and neural dysfunctions over time remains incompletely understood. Here we characterize the longitudinal effect of social defeat on goal-directed actions and prefrontal cortical activity in mice, using a head-fixed sucrose preference task and two-photon calcium imaging. Behaviorally, stress-induced loss of reward sensitivity intensifies over days. Motivational anhedonia, the failure to translate positive reinforcements into future actions, requires multiple sessions of stress exposure to become fully established. For neural activity, individual layer 2/3 pyramidal neurons in the Cg1 and M2 subregions of the medial prefrontal cortex have heterogeneous responses to stress. Changes in ensemble activity differ significantly between susceptible and resilient animals after the first defeat session, and continue to diverge following successive stress episodes before reaching persistent abnormal levels. Collectively, these results demonstrate that the cumulative impact of an ethologically relevant stress can be observed at the level of cellular activity of individual prefrontal neurons. The distinct neural responses associated with resilience versus susceptibility raises the hypothesis that the negative impact of social stress is neutralized in resilient animals, in part through an adaptive reorganization of prefrontal cortical activity.

neuroscience↗