Biology subjects

Marcinkiewcz, C.

Publications and source records attributed to Marcinkiewcz, C..

5 recordsLinked to original sources

bioRxiv2026

Adolescent Social Isolation Facilitates Tau Spread in Raphe Nuclei Linking Depression and Hyperalgesia in Alzheimers Disease

Tau pathology in brainstem serotonergic circuits drives early neuropsychiatric dysfunction in Alzheimers disease (AD), yet mechanisms linking the exposome, particularly social stress exposures to depression and altered pain perception, remain unclear. Here, we demonstrate that adolescent social isolation, a critical psychosocial exposome factor and major trigger of depression, facilitates tau propagation in the dorsal raphe nucleus (DRN) and downstream raphe nuclei, producing both neuropsychiatric and pain-related sequelae. Tau[P301L] was transduced into the DRN of 30-day socially isolated or group housed C57BL/6J mice using AAV, with control mice receiving AAV-GFP. Four weeks post-transduction, anxiety, social behavior, and pain sensitivity were assessed, and phosphorylated tau (ptau) within the DRN and spread to the median raphe (MRN) and raphe magnus (RMg) serotonergic neurons were evaluated. Socially isolated tau[P301L] mice exhibited hyperlocomotion, anxiety-like behavior, social deficits and hyperalgesia. Histological analysis revealed elevated ptau within TPH2 neurons in the DRN and trans-synaptic tau spread to MRN and RMg, accompanied by reduced TPH2 and increased ptau at the downstream raphe nuclei. Fluorescence in situ hybridization confirmed altered expression of Slc6a4 and Tgm2, a stress-responsive gene implicated in AD. These results indicate that DRN tau under social stress drives neuropsychiatric phenotypes, while tau spread to MRN and RMg disrupts serotonergic modulation of pain. This study provides the first evidence that adolescent stress promotes tau propagation within the raphe nuclei, linking early neuropsychiatric and pain-processing deficits to prodromal Alzheimers disease and identifying a critical pathway through which psychosocial exposome risk converges with tau pathology to enable early intervention.

neuroscience↗

bioRxiv2025

The superficial tufted and mitral cell output neurons of the mouse olfactory bulb have a dual role in insulin sensing

The olfactory bulb (OB) contains multiple, parallel projection neurons to relay the nature of a stimulus. In a mouse ex vivo slice preparation, we used patch-clamp electrophysiology to measure intrinsic properties, excitability, action potential (AP) shape, voltage-activated conductances, and neuromodulation in the newly-categorized superficial tufted cells (sTCs) compared with those of mitral cells (MCs). We propose that a marked difference in voltage-dependent current represents distinct ion channel populations that affect the kinetics of action potentials, and evokes an increase in sTC firing frequency, albeit both types of projection neurons having similar AP spiking activity. Triple-colored immunofluorescence and RNA scope were used to detect co-localization of the Kv1.3 ion channel and the insulin receptor in sTCs, with [~]73% of sTCs expressing both. The sTCs were modulated by bath application of insulin - increasing AP firing frequency by 97%, attributable to an 8% decrease in the intraburst interval, and a reduction of the latency to first spike by 37%. We conclude that there may be a range of neuromodulators of sTCs that may alter excitability and fine-tune olfactory information processing or metabolic balance. SUMMARY STATEMENTSuperficial tufted cells, as output neurons of the olfactory bulb, were electrophysiologically studied to be insulin sensitive. Brain insulin signaling represents a manner in which olfactory and metabolic circuitry are intertwined.

neuroscience↗

bioRxiv2023

Lateral Septal Circuits Govern Schizophrenic-Like Effects of Ketamine on Social Behavior

Schizophrenia is marked by poor social functioning that can have a severe impact on quality of life and independence, but the underlying neural circuity is not well understood. Here we used a translational model of subanesthetic ketamine in mice to delineate neural pathways in the brain linked to social deficits in schizophrenia. Mice treated with chronic ketamine (30 mg/kg/day for 10 days) exhibit profound social and sensorimotor deficits as previously reported. Using three- dimensional c-Fos immunolabeling and volume imaging (iDISCO), we show that ketamine treatment resulted in hypoactivation of the lateral septum (LS) in response to social stimuli. Chemogenetic activation of the LS rescued social deficits after ketamine treatment, while chemogenetic inhibition of previously active populations in the LS (i.e. social engram neurons) recapitulated social deficits in ketamine-naive mice. We then examined the translatome of LS social engram neurons and found that ketamine treatment dysregulated genes implicated in neuronal excitability and apoptosis, which may contribute to LS hypoactivation. We also identified 38 differentially expressed genes (DEGs) in common with human schizophrenia, including those involved in mitochondrial function, apoptosis, and neuroinflammatory pathways. Chemogenetic activation of LS social engram neurons induced downstream activity in the ventral part of the basolateral amygdala, subparafascicular nucleus of the thalamus, intercalated amygdalar nucleus, olfactory areas, and dentate gyrus, and it also reduces connectivity of the LS with the piriform cortex and caudate-putamen. In sum, schizophrenia-like social deficits may emerge via changes in the intrinsic excitability of a discrete subpopulation of LS neurons that serve as a central hub to coordinate social behavior via downstream projections to reward, fear extinction, motor and sensory processing regions of the brain.

neuroscience↗

bioRxiv2023

Involvement of a serotonin/GLP-1 circuit in adolescent isolation-induced diabetes

In 2020, stay-at-home orders were implemented to stem the spread of SARS-CoV-2 worldwide. Social isolation can be particularly harmful to children and adolescents--during the pandemic, the prevalence of obesity increased by [~]37% in persons aged 2-19. Obesity is often comorbid with type 2 diabetes, which was not assessed in this human pandemic cohort. Here, we investigated whether male mice isolated throughout adolescence develop type 2 diabetes in a manner consistent with human obesity-induced diabetes, and explored neural changes that may underlie such an interaction. We find that isolating C57BL/6J mice throughout adolescence is sufficient to induce type 2 diabetes. We observed fasted hyperglycemia, diminished glucose clearance in response to an insulin tolerance test, decreased insulin signaling in skeletal muscle, decreased insulin staining of pancreatic islets, increased nociception, and diminished plasma cortisol levels compared to group-housed control mice. Using Promethion metabolic phenotyping chambers, we observed dysregulation of sleep and eating behaviors, as well as a time-dependent shift in respiratory exchange ratio of the adolescent-isolation mice. We profiled changes in neural gene transcription from several brain areas and found that a neural circuit between serotonin-producing and GLP-1-producing neurons is affected by this isolation paradigm. Overall, spatial transcription data suggest decreased serotonin neuron activity (via decreased GLP-1-mediated excitation) and increased GLP-1 neuron activity (via decreased serotonin-mediated inhibition). This circuit may represent an intersectional target to further investigate the relationship between social isolation and type 2 diabetes, as well as a pharmacologically-relevant circuit to explore the effects of serotonin and GLP-1 receptor agonists. Article HighlightsO_LIIsolating C57BL/6J mice throughout adolescence is sufficient to induce type 2 diabetes, presenting with fasted hyperglycemia. C_LIO_LIAdolescent-isolation mice have deficits in insulin responsiveness, impaired peripheral insulin signaling, and decreased pancreatic insulin production. C_LIO_LITranscriptional changes across the brain include the endocannabinoid, serotonin, and GLP-1 neurotransmitters and associated receptors. C_LIO_LIThe neural serotonin/GLP-1 circuit may represent an intersectional target to further investigate the relationship between social isolation and type 2 diabetes. Serotonin-producing neurons of adolescent-isolation mice produce fewer transcripts for the GLP-1 receptor, and GLP-1 neurons produce fewer transcripts for the 5-HT1A serotonin receptor. C_LI

neuroscience↗

bioRxiv2021

Adolescent ethanol drinking promotes hyperalgesia, neuroinflammation and serotonergic deficits in mice that persist into adulthood

Adolescent alcohol use can permanently alter brain function and lead to poor health outcomes in adulthood. Emerging evidence suggests that alcohol use predispose to pain disorders or exacerbate existing pain conditions, but the neural mechanisms are currently unknown. Here we report that mice exposed to adolescent intermittent access to ethanol (AIE) exhibit increased pain sensitivity and depressive-like behaviors that persist after alcohol cessation and are accompanied by elevated CD68 expression in microglia and reduced numbers of serotonin (5-HT)-expressing neurons in the dorsal raphe nucleus (DRN). 5-HT expression was also reduced in the thalamus, anterior cingulate cortex (ACC) and amygdala as well as the lumbar dorsal horn of the spinal cord. We then found that chronic minocycline administration after AIE alleviated hyperalgesia and social deficits, while chemogenetic activation of microglia in the DRN of Cx3cr1-cre-GFP mice reproduced the effects of AIE on pain and social interaction. Taken together, these results indicate that microglial activation in the DRN may be a primary driver of pain and negative affect after AIE.

neuroscience↗