Biology subjects

Wichmann, R.

Publications and source records attributed to Wichmann, R..

6 recordsLinked to original sources

bioRxiv2025

Social Exclusion Amplifies Behavioral Responses to Physical Pain via Insular Neuromodulation

The "Pain Overlap Theory" (1) proposes that the experience of social pain overlaps with and amplifies the experience of physical pain by sharing parts of the same underlying processing systems (2-6). In humans, the insular cortex has been implicated in this overlap of physical and social pain, but a mechanistic link has not been made (2,4,5,7-9). To determine whether social pain can subsequently impact responses to nociceptive stimuli via convergent electrical signals (spikes) or convergent chemical signals (neuromodulators), we designed a novel Social Exclusion paradigm termed the Fear of Missing Out (FOMO) Task which facilitates a mechanistic investigation in mice. We found that socially-excluded mice display more severe responses to physical pain, disrupted valence encoding, and impaired neural representations of nociceptive stimuli. We performed a systematic biosensor panel and found that endocannabinoid and oxytocin signaling in the insular cortex have opposing responses during trials where mice were attending or not attending to the Social Exclusion events respectively, demonstrating distinct neuromodulatory substrates that underpin different states of Social Exclusion. We also found that intra-insular blockade of oxytocin signaling increased the response to physical pain following Social Exclusion. Together these findings suggest Social Exclusion effectively alters physical pain perception using neuromodulatory signaling in the insular cortex.

neuroscience↗

bioRxiv2025

Separable Dorsal Raphe Dopamine Projections mediate the Facets of Loneliness-like state

Affiliative social connections facilitate well-being and survival in numerous species. Engaging in social interactions requires positive or negative motivational drive, elicited through coordinated activity across neural circuits. However, the identity, interconnectivity, and functional encoding of social information within these circuits remains poorly understood. Here, we focus on downstream projections of dorsal raphe nucleus (DRN) dopamine neurons (DRNDAT), which we previously implicated in social motivation alongside an aversive affective state. We show that three prominent DRNDAT projections - to the bed nucleus of the stria terminalis (BNST), central amygdala (CeA), and posterior basolateral amygdala (BLP) - play separable roles in behavior, despite substantial collateralization. Photoactivation of the DRNDAT-CeA projection promoted social behavior and photostimulation of the DRNDAT-BNST projection promoted exploratory behavior, while the DRNDAT-BLP projection supported place avoidance, suggesting a negative affective state. Downstream regions showed diverse receptor expression, poising DRNDAT neurons to act through dopamine, neuropeptide, and glutamate transmission. Furthermore, we show ex vivo that the effect of DRNDAT photostimulation on downstream neuron excitability depended on region and baseline cell properties, resulting in excitatory responses in BNST cells and diverse responses in CeA and BLP. Finally, in vivo microendoscopic cellular-resolution recordings in the CeA with DRNDAT photostimulation revealed a correlation between social behavior and neurons excited by social stimuli- suggesting that increased dopamine tone may recruit different CeA neurons to social ensembles. Collectively, these circuit features may facilitate a coordinated, but flexible, response in the presence of social stimuli that can be flexibly guided based on the internal social homeostatic need state of the individual.

neuroscience↗

bioRxiv2024

Predicting Future Development of Stress-Induced Anhedonia From Cortical Dynamics and Facial Expression

The current state of mental health treatment for individuals diagnosed with major depressive disorder leaves billions of individuals with first-line therapies that are ineffective or burdened with undesirable side effects. One major obstacle is that distinct pathologies may currently be diagnosed as the same disease and prescribed the same treatments. The key to developing antidepressants with ubiquitous efficacy is to first identify a strategy to differentiate between heterogeneous conditions. Major depression is characterized by hallmark features such as anhedonia and a loss of motivation (1, 2), and it has been recognized that even among inbred mice raised under identical housing conditions, we observe heterogeneity in their susceptibility and resilience to stress (3). Anhedonia, a condition identified in multiple neuropsychiatric disorders, is described as the inability to experience pleasure and is linked to anomalous medial prefrontal cortex (mPFC) activity (4). The mPFC is responsible for higher order functions (5-8), such as valence encoding; however, it remains unknown how mPFC valence-specific neuronal population activity is affected during anhedonic conditions. To test this, we implemented the unpredictable chronic mild stress (CMS) protocol (9-11) in mice and examined hedonic behaviors following stress and ketamine treatment. We used unsupervised clustering to delineate individual variability in hedonic behavior in response to stress. We then performed in vivo 2-photon calcium imaging to longitudinally track mPFC valence-specific neuronal population dynamics during a Pavlovian discrimination task. Chronic mild stress mice exhibited a blunted effect in the ratio of mPFC neural population responses to rewards relative to punishments after stress that rebounds following ketamine treatment. Also, a linear classifier revealed that we can decode susceptibility to chronic mild stress based on mPFC valence-encoding properties prior to stress-exposure and behavioral expression of susceptibility. Lastly, we used a markerless pose tracking computer vision tool, SLEAP (31), to predict whether a mouse would become resilient or susceptible based on facial expressions during a Pavlovian discrimination task. These results indicate that mPFC valence encoding properties and behavior are predictive of anhedonic states. Altogether, these experiments point to the need for increased granularity in the measurement of both behavior and neural activity, as these factors can predict the predisposition to stress-induced anhedonia.

neuroscience↗

bioRxiv2022

Amygdalostriatal transition zone neurons encode sustained valence to direct conditioned behaviors

To ensure survival, the brain must rapidly identify threats and maintain defensive behaviors for as long as danger is present. The amygdala has been studied as a key site for fear responses, but responses to threat cues in amygdala neurons are largely transient and shorter in duration than defensive responses observed. Here, we present the amygdalostriatal transition zone (ASt) as a missing piece of the circuits mediating fear responses. Using single-nucleus RNA sequencing (snRNA-seq), we demonstrate that the ASt is genetically distinct from adjacent striatal and amygdalar structures. In vivo electrophysiology and calcium imaging reveal that ASt neurons have robust, sustained responses to shock-predicting cues. Further, photostimulation of the ASt is sufficient to drive freezing and avoidance behaviors, and optogenetic inhibition experiments show that Drd2+ ASt neurons are necessary for cue-conditioned fear responses. Our findings establish the ASt as a previously unappreciated yet critical structure for encoding learned associations and directing defensive behaviors.

neuroscience↗

bioRxiv2022

Thalamus sends information about arousal but not valence to the amygdala

RationaleThe basolateral amygdala (BLA) and medial geniculate nucleus of the thalamus (MGN) have both been shown to be necessary for the formation of associative learning. While the role that the BLA plays in this process has long been emphasized, the MGN has been less well-studied and surrounded by debate regarding whether the relay of sensory information is active or passive. ObjectivesWe seek to understand the role the MGN has within the thalamoamgydala circuit in the formation of associative learning. MethodsHere, we use optogenetics to dissect the MGN-BLA circuit and explore the specific subpopulations for evidence of learning and synthesis of information that could impact downstream BLA encoding. We employ various machine learning techniques to investigate function within neural subpopulations. We introduce a novel method to investigate tonic changes across trial-by-trial structure, which offers an alternative approach to traditional trial-averaging techniques. ResultsWe find that the MGN appears to encode arousal but not valence, unlike the BLA which encodes for both. We find that the MGN and the BLA appear to react differently to expected and unexpected outcomes; the BLA biased responses toward reward prediction error and the MGN focused on anticipated punishment. We uncover evidence of tonic changes by visualizing changes across trials during inter-trial intervals (baseline epochs) for a subset of cells. ConclusionWe conclude that the MGN-BLA projector population acts as both filter and transferer of information by relaying information about the salience of cues to the amygdala, but these signals are not valence-specified. PrefaceIn tribute to Nadia Chaudhri, and her discoveries regarding how contexts can modulate the representation of cues in the amygdala (Sciascia et al., 2015), and other mesolimbic circuit components (Chaudhri et al., 2009, 2008; Valyear et al., 2020), here we explore what information processing precedes entry into the basolateral amygdala (BLA) from the thalamus and develop visualization approaches for exploring across-trial temporal dynamics in addition to within-trial population activity.

neuroscience↗

bioRxiv2017

Acute stress induces long-lasting alterations in the dopaminergic system of female mice

Stress is a risk factor for many neuropsychiatric disorders, and the mesolimbic dopamine (DA) pathway is a crucial node of vulnerability. Despite the high prevalence of stress-related neuropsychiatric disorders in women, preclinical knowledge on the impact of stress on neural circuitry has predominantly been acquired in males. Here, we examine how a non-social stressor impacts the effect of DA neurotransmission on social and reward-related behaviors in female mice. Acute stress exposure attenuated the anti-social effects of photoinhibiting ventral tegmental area (VTA) DA neurons and transformed photoactivation of these cells into an anti-social signal. Fast-scan cyclic voltammetry (FSCV) revealed an enhancement in optogenetically-induced DA release after stress. 60 days after stress, mice showed distinct patterns of intra-cranial self-stimulation of VTA DA neurons. Our results reveal the impact stress exerts on females and show that neural and behavioral changes induced by acute stress exposure are still present months later.

neuroscience↗