Biology subjects

Pittenger, C.

Publications and source records attributed to Pittenger, C..

15 recordsLinked to original sources

bioRxiv2026

The Limbic Overload Hypothesis of Hypomanic Vulnerability: A Dynamic Biosocial Perspective

Hypomanic tendencies are associated with elevated goal-directed behavior, creativity, charisma, sociability, and entrepreneurial drive, but also with mood instability, irritability, impulsive persistence, and elevated risk for bipolar disorder and other psychopathology. Existing models often emphasize unidimensional constructs such as reward sensitivity or behavioral activation, yet these approaches incompletely capture the dynamic and often contradictory nature of the hypomanic temperament. We propose the Limbic Overload Hypothesis of Hypomanic Vulnerability, a dynamic biosocial framework suggesting that hypomanic tendencies reflect a persistent pattern of elevated engagement despite potential loss, coupled with reduced integration of negative emotional experience into subsequent behavioral regulation. Over time, this pattern may contribute to progressive "limbic overload," characterized by increasing emotional dysregulation, hypersensitivity to salient experiences, and vulnerability to psychopathology. Integrating evidence from personality research, affective neuroscience, and preliminary neuroimaging findings, we propose a dynamic cortico-limbic model linking prefrontal-limbic coordination, loss tolerance, emotional updating, and social reinforcement cycles. Preliminary pilot data suggest that individual differences in hypomanic tendencies are reflected not simply in baseline cortico-limbic organization, but in dynamic neural reconfiguration across pre-task resting-state [->] task [->] post-task resting-state transitions during loss-related decision making. Specifically, elevated hypomanic tendencies were associated with persistently elevated tolerance of potential losses and reduced integration of negative emotional information into subsequent behavioral regulation. We further propose that social connectedness and cognitive-emotional integration may mitigate progressive limbic overload and contribute to resilience. Together, this framework generates experimentally testable predictions regarding the neural, behavioral, and social processes underlying hypomanic vulnerability and resilience.

neuroscience↗

bioRxiv2026

Human claustrum neurons encode uncertainty and prediction errors during aversive learning

Flexible behavior depends on continuous updating of internal models, yet the neural circuits coordinating this process remain poorly understood [1]. The claustrum -- reciprocally connected to nearly the entire neocortex -- is uniquely positioned to influence cortical processing. Here we report single-neuron recordings from the human claustrum during aversive learning [2], with anterior cingulate cortex and amygdala recordings for comparison. Claustrum and anterior cingulate neurons displayed structured, task-related responses. Distinct subpopulations encoded stimulus onset and action-contingent outcomes, with outcome representations diverging between regions. Critically, both regions encoded model-derived latent variables -- uncertainty and prediction error -- but with different temporal profiles: only the anterior cingulate carried uncertainty signals during the intertrial period, while both regions encoded uncertainty and prediction error during the active-avoidance period. The amygdala, by contrast, showed minimal latent-variable modulation. These findings provide evidence that human claustrum neurons track higher-order cognitive variables not directly observable from sensory input, and reveal dissociable roles for the claustrum and anterior cingulate cortex in tracking latent task states.

neuroscience↗

bioRxiv2026

Enhancing cGMP signaling with psilocybin reduces head twitch and restructures the synaptic proteome while maintaining antidepressant response

Psilocybin has antidepressant effects, but its 5-HT2AR-mediated perceptual effects limit tolerability. We combined psilocybin with a phosphodiesterase-9 inhibitor (PDE9i) and observed suppression of head-twitch response, but maintenance of antidepressant-like behavior. Proteomics showed that PDE9i-psilocybin reduced 5-HT2AR-mediated pathways while enhancing synaptogenesis. These results suggest that PDE9i-psilocybin represents a promising therapeutic strategy.

neuroscience↗

bioRxiv2026

MDMA enhances prefrontal plasticity and representational drift during fear extinction

Fear extinction requires dynamic updating of cortical representations, yet the neural mechanisms underlying successful extinction remain poorly understood. Some psychoactive substances induce structural plasticity in medial prefrontal cortex (mPFC), possibly underlying their therapeutic potential. Here we investigated whether MDMA, which enhances fear extinction, induces prefrontal structural and functional plasticity, and measured its effects on ensemble representations during extinction. Longitudinal two-photon microscopy revealed that MDMA increased spine density and spinogenesis across prefrontal subregions. Miniscope Ca{superscript 2} imaging in infralimbic cortex (IL) during fear extinction revealed that IL became more correlated with the suppression of freezing behavior, consistent with a strengthening of its role in extinction. Longitudinal cell registration demonstrated accelerated representational drift across days in MDMA-treated mice; this effect was strongest in a functionally defined subpopulation of neurons that showed suppression of activity to conditioned cues. These findings demonstrate that MDMA facilitates structural and functional neuroplasticity, potentially underlying its enhancement of extinction learning.

neuroscience↗

bioRxiv2026

Value-Based Evidence Accumulation as a Transdiagnostic Marker of General Distress

General distress cuts across psychiatric symptom domains, yet its computational correlates remain poorly defined. We examined whether drift rate--a core parameter indexing the efficiency of evidence accumulation--is more strongly associated with general distress than with domain-specific symptoms. In a cross-sectional online sample of 441 adults from the general population, participants completed a perceptual and value-based decision-making task, symptom assessments, and cognitive testing. Drift rates were estimated using hierarchical drift-diffusion modeling. Individuals with severe symptom elevations showed robust reductions in drift rate, particularly for value-based decisions. Mixed-effects models demonstrated that general distress, indexed by the Positive Symptom Distress Index, was more strongly associated with value-based than perceptual drift rate, even after accounting for all symptom domains. Value-based drift rate also explained variance in general distress beyond that accounted for by elevated symptoms across domains and selectively attenuated associations with somatization and paranoid symptoms. These findings suggest that value-based evidence accumulation captures a transdiagnostic component of distress-related impairment that is not reducible to symptom burden alone.

pathology↗

bioRxiv2025

Beta bursts mediate amygdala gating of hippocampal emotional encoding

The amygdala and hippocampus are key structures in emotional processing, yet the transient neural dynamics coordinating their interaction remain poorly understood. We simultaneously recorded single-neuron activity and local field potentials from these regions in epilepsy patients performing an emotional image-rating task. Neurons in both areas exhibited firing rate changes predictive of subjective emotional valence. While conventional spectral analysis revealed no valence-specific patterns, beta bursts (13-30 Hz)--transient, high-power events-were uniquely modified by task features. In both regions, beta bursts were associated with increased gamma amplitude and enhanced phase coherence, with beta-gamma phase-amplitude coupling capturing emotion-related dynamics. Critically, amygdala beta bursts were associated with strong suppression of hippocampal firing, coinciding with interneuron activation, during negative valence/highest arousal processing, whereas hippocampal bursts showed no reciprocal influence. These findings suggest that beta bursts may represent a temporally precise neural correlate of emotional appraisal and a candidate mechanism for targeted neuromodulation in mood disorders.

neuroscience↗

bioRxiv2024

Circuit mechanisms underlying sexually dimorphic outcomes of early life stress

Stress during early life influences brain development and can affect social, motor, and emotional processes. We describe a striking sex difference in the effects of early life stress (ELS), which produces anhedonia and anxiety-like behaviors in female adolescent mice, as reported previously, but repetitive behavioral pathology and social deficits in male adolescent mice. Notably, this parallels sex differences seen in the prevalence of psychiatric symptoms: depression and anxiety disorders are more common in girls and women, whereas neurodevelopmental disorders like autism spectrum disorder and Tourette syndrome are markedly more common in boys and men. We characterized the effects of ELS on the medial prefrontal cortex (mPFC) and on its projections to the dorsal striatum (dStr) and lateral septum (LS). ELS males, but not females, developed hyperactivity in the cortico-striatal circuit and hypoactivity in the cortico-septal circuit. Chemogenetic manipulation of cortico-striatal projection neurons modulates repetitive behavioral pathology and social behaviors in stressed males, and anhedonia in stressed females. Activation of cortico-septal projection neurons rescues social deficits in stressed males. We conclude that early life stress produces sexually dimorphic behavioral effects, with potential relevance to human psychiatric symptoms, through its differential effects on cortico-striatal and cortico-septal circuits.

neuroscience↗

bioRxiv2024

Sexual dimorphism in histamine regulation of striatal dopamine

Dopamine modulation of the basal ganglia differs in males and females and is implicated in numerous neuropsychiatric conditions, including some, like Tourette Syndrome (TS) and attention deficit hyperactivity disorder (ADHD), that have marked sex differences in prevalence. Genetic studies in TS and subsequent work in animals suggest that a loss of histamine may contribute to dysregulation of dopamine. Motivated by this, we characterized the modulation of striatal dopamine by histamine, using microdialysis, targeted pharmacology, and shRNA knockdown of histamine receptors. Intracerebroventricular (ICV) histamine reduced striatal dopamine in male mice, replicating previous work. In contrast, and unexpectedly, ICV histamine increased striatal dopamine in females. ICV or targeted infusion of agonists revealed that the effect in males depends on H2R receptors in the substantia nigra pars compacta (SNc). Knockdown of H2R in SNc GABAergic neurons abrogated the effect, identifying these cells as a key locus of histamines regulation of dopamine in males. In females, however, H2R had no discernible role; instead, H3R agonists in the striatum increased striatal dopamine. Strikingly, the effect of histamine on dopamine in females was modulated by the estrous cycle, appearing only in estrus/proestrus, when estrogen levels are high. These findings confirm the regulation of striatal dopamine by histamine but identify marked sexual dimorphism in and estrous modulation of this effect. These findings may shed light on the mechanistic underpinnings of sex differences in the striatal circuitry, and in several neuropsychiatric conditions. Significance StatementDysregulation of the basal ganglia contributes to the pathophysiology of numerous neuropsychiatric diseases, including several, such as Tourette syndrome (TS), that are characterized by sex differences. Previous genetic studies in humans identified histamine dysregulation as a potential to the development of TS; follow-up work in mice highlighted the role of histamine in regulating striatal dopamine tone. Striatal dopamine dysregulation has been implicated in numerous neuropsychiatric disorders, including TS, schizophrenia, and attention deficit-hyperactivity disorder. Here, we uncover novel and significant sex differences in histamine regulation of dopaminergic modulation of the striatum. A better understanding of these differences may provide insight into the mechanisms underlying sex-dependent outcomes in neuropsychiatric disease.

neuroscience↗

bioRxiv2024

Sexual dimorphism in the distribution and density of regulatory interneurons in the striatum

Dysfunction of the cortico-basal circuitry - including its primary input nucleus, the striatum - contributes to neuropsychiatric disorders, including autism and Tourette Syndrome (TS). These conditions show marked sex differences, occurring more often in males than in females. Regulatory interneurons, including cholinergic interneurons (CINs) and parvalbumin-expressing GABAergic fast spiking interneurons (FSIs), are implicated in human neuropsychiatric disorders such as TS, and ablation of these interneurons produces relevant behavioral pathology in male mice, but not in females. Here we investigate sex differences in the density and distribution of striatal interneurons, using stereological quantification of CINs, FSIs, and somatostatin-expressing (SOM) GABAergic interneurons in the dorsal striatum (caudate-putamen) and the ventral striatum (nucleus accumbens) in male and female mice. Males have a higher density of CINs than females, especially in the dorsal striatum; females have equal distribution between dorsal and ventral striatum. FSIs showed similar effects, with a greater dorsal-ventral density gradient in males than in females. SOM interneurons were denser in the ventral than in the dorsal striatum, with no sex differences. These sex differences in the density and distribution of FSIs and CINs may contribute to sex differences in basal ganglia function, including in the context of psychopathology.

neuroscience↗

bioRxiv2024

The human claustrum tracks slow waves during sleep

Slow waves are a distinguishing feature of non-rapid-eye-movement (NREM) sleep, an evolutionarily conserved process critical for brain function. Non-human studies posit that the claustrum, a small subcortical nucleus, coordinates slow waves. We recorded claustrum neurons in humans during sleep. In contrast to neurons from other brain regions, claustrum neurons increased their activity and tracked slow waves during NREM sleep suggesting that the claustrum plays a role in human sleep architecture.

neuroscience↗

bioRxiv2023

A novel naive Bayes approach to identifying grooming behaviors in the force-plate actometric platform

BackgroundSelf-grooming behavior in rodents serves as a valuable model for investigating stereotyped and perseverative responses. Most current grooming analyses primarily rely on video observation, which lacks standardization, efficiency, and quantitative information about force. To address these limitations, we developed an automated paradigm to analyze grooming using a force-plate actometer. New MethodGrooming behavior is quantified by calculating ratios of relevant movement power spectral bands. These ratios are then input into a naive Bayes classifier, trained with manual video observations. To validate the effectiveness of this method, we applied it to the behavioral analysis of the early-life striatal cholinergic interneuron depletion (CIN-d) mouse, a model of tic pathophysiology recently developed in our laboratory, which exhibits prolonged grooming responses to acute stressors. Behavioral monitoring was simultaneously conducted on the force-place actometer and by video recording. ResultsThe naive Bayes approach achieved 93.7% accurate classification and an area under the receiver operating characteristic curve of 0.894. We confirmed that male CIN-d mice displayed significantly longer grooming durations compared to controls. However, this elevation was not correlated with increases in grooming force. Notably, haloperidol, a benchmark therapy for tic disorders, reduced both grooming force and duration. Comparison with Existing MethodsIn contrast to observation-based approaches, our method affords rapid, unbiased, and automated assessment of grooming duration, frequency, and force. ConclusionsOur novel approach enables fast and accurate automated detection of grooming behaviors. This method holds promise for high-throughput assessments of grooming stereotypies in animal models of tic disorders and other psychiatric conditions.

neuroscience↗

bioRxiv2023

Prefrontal Cortex Astroglia Modulate Anhedonia-like Behavior

Reductions of astroglia expressing glial fibrillary acidic protein (GFAP) are consistently found in the prefrontal cortex (PFC) of patients with depression and in rodent chronic stress models. Here, we examine the consequences of PFC GFAP+ cell depletion and cell activity enhancement on depressive-like behaviors in rodents. Using viral expression of diphtheria toxin receptor in PFC GFAP+ cells, which allows experimental depletion of these cells following diphtheria toxin administration, we demonstrated that PFC GFAP+ cell depletion induced anhedonia-like behavior within 2 days and lasting up to 8 days, but no anxiety-like deficits. Conversely, activating PFC GFAP+ cell activity for 3 weeks using designer receptor exclusively activated by designer drugs (DREADDs) reversed chronic restraint stress-induced anhedonia-like deficits, but not anxiety-like deficits. Our results highlight a critical role of cortical astroglia in the development of anhedonia and further support the idea of targeting astroglia for the treatment of depression.

neuroscience↗

bioRxiv2022

5-MeO-DMT modifies innate behaviors and promotes structural neural plasticity in mice

Serotonergic psychedelics are gaining increasing interest as potential therapeutics for a range of mental illnesses. Compounds with short-lived subjective effects may be clinically useful because dosing time would be reduced, which may improve patient access. One short-acting psychedelic is 5-MeO-DMT, which has been associated with improvement in depression and anxiety symptoms in early clinical studies. However relatively little is known about the behavioral effects and neural mechanisms of 5-MeO-DMT in animal models. Here we characterized the effects of 5-MeO-DMT on innate behaviors and dendritic architecture in mice. We showed that 5-MeO-DMT induces a dose-dependent increase in head-twitch response that is shorter in duration than that induced by psilocybin at all doses tested. 5-MeO-DMT also substantially suppresses social ultrasonic vocalizations produced during mating behavior. 5-MeO-DMT produces long-lasting increases in dendritic spine density in the mouse medial frontal cortex that are driven by an elevated rate of spine formation. However, unlike psilocybin, 5-MeO-DMT did not affect the size of dendritic spines. These data provide insights into the behavioral and neural consequences underlying the action of 5-MeO-DMT and highlight similarities and differences with those of psilocybin.

neuroscience↗

bioRxiv2020

Inhibitory regulation of calcium transients in prefrontal dendritic spines is compromised by a nonsense Shank3 mutation

The SHANK3 gene encodes a postsynaptic scaffold protein in excitatory synapses, and its disruption is implicated in neurodevelopmental disorders such as Phelan-McDermid syndrome, autism spectrum disorder, and schizophrenia. Most studies of SHANK3 in the neocortex and hippocampus have focused on disturbances in pyramidal neurons. However, GABAergic interneurons likewise receive excitatory inputs and presumably would also be a target of constitutive SHANK3 perturbations. In this study, we characterize the prefrontal cortical microcircuit in awake mice using subcellular-resolution two-photon microscopy. We focused on a nonsense R1117X mutation, which leads to truncated SHANK3 and has been linked previously to cortical dysfunction. We find that R1117X mutants have abnormally elevated calcium transients in apical dendritic spines. The synaptic calcium dysregulation is due to a loss of dendritic inhibition via decreased NMDAR currents and reduced firing of dendrite-targeting somatostatin-expressing (SST) GABAergic interneurons. Notably, upregulation of the NMDAR subunit GluN2B in SST interneurons corrects the excessive synaptic calcium signals and ameliorates learning deficits in R1117X mutants. These findings reveal dendrite-targeting interneurons, and more broadly the inhibitory control of dendritic spines, as a key microcircuit mechanism compromised by the SHANK3 dysfunction.

neuroscience↗

bioRxiv2019

Ketamine disinhibits dendrites and enhances calcium signals in prefrontal dendritic spines

A subanesthetic dose of ketamine causes acute psychotomimetic symptoms and then more sustained antidepressant effects. A key targeted brain region is the prefrontal cortex, and the prevailing disinhibition hypothesis posits that N-methyl-d-aspartate receptor (NMDAR) antagonists such as ketamine may act preferentially on GABAergic neurons. However, cortical GABAergic neurons are heterogeneous. In particular, somatostatin-expressing (SST) interneurons selectively inhibit dendrites and regulate synaptic inputs, yet their response to systemic NMDAR antagonism is unknown. Here, we report that administration of ketamine acutely suppresses the activity of SST interneurons in the medial prefrontal cortex of the awake mouse. The deficient dendritic inhibition leads to greater synaptically evoked calcium transients in the apical dendritic spines of pyramidal neurons. By manipulating NMDAR signaling via GluN2B knockdown, we show that ketamines actions on the dendritic inhibitory mechanism has ramifications for frontal cortex-dependent behaviors and cortico-cortical connectivity. Collectively, these results demonstrate dendritic disinhibition and elevated calcium levels in dendritic spines as important local-circuit alterations driven by the administration of subanesthetic ketamine.

neuroscience↗