Biology subjects

Marcinkiewcz, C. A.

Publications and source records attributed to Marcinkiewcz, C. A..

5 recordsLinked to original sources

bioRxiv2024

A new insight into the role of CART peptide in serotonergic function and anxiety

Cocaine and amphetamine-regulated transcript (CART) peptide has been established as a contributor to anxiogenic behavior. Genetic mutations in the CART gene are associated with anxiety and depression, and increased CART expression has been reported in suicide victims. Extensive research has focused on the role of CART peptide in mesolimbic neurocircuitry, but its involvement in the dorsal raphe nucleus (DRN) and serotonin (5HT) system remains unexplored. Here we demonstrate that CART processes are proximal to 5HTDRN neurons and that microinjection of CART (55-102) peptide into the DRN has an anxiogenic effect in mice. Furthermore, central CART administration reduced cfos activation in 5HT neurons of the ventral DRN, which is a putative reward/anti-stress circuit. The inhibitory effect of CART on 5HTDRN neuronal function and local 5HT release is further demonstrated with in vivo fiber photometry coupled with calcium and 5HT biosensors and by mass spectrometry. Moreover, using Cre-dependent retrograde tracing, we observed DRN-projecting CART neurons in the Edinger Westphal nucleus (EW), nucleus accumbens (NAc), and various hypothalamic nuclei including the ventromedial hypothalamus (VMH). Interestingly, based on ex vivo electrophysiological recordings, acute stress increased excitability in DRN-projecting CART neurons located in the EW, but not in the VMH or NAc. This suggests that the stress may promote anxiety-like behavior by activating the EWCART[->]5HTDRN circuit that ultimately inhibits 5HT transmission. In sum, understanding the intricate dynamics of the CARTergic and 5HTergic systems proves crucial in addressing 5HT-related dysfunctions, providing invaluable insights into both health and disease.

neuroscience↗

bioRxiv2023

Alcohol inhibits sociability via serotonin inputs to the nucleus accumbens

Social interaction is a core component of motivational behavior that is perturbed across multiple neuropsychiatric disorders, including alcohol use disorder (AUD). Positive social bonds are neuroprotective and enhance recovery from stress, so reduced social interaction in AUD may delay recovery and lead to alcohol relapse. We report that chronic intermittent ethanol (CIE) induces social avoidance in a sex-dependent manner and is associated with hyperactivity of serotonin (5-HT) neurons in the dorsal raphe nucleus (DRN). While 5-HTDRN neurons are generally thought to enhance social behavior, recent evidence suggests that specific 5-HT pathways can be aversive. Using chemogenetic iDISCO, the nucleus accumbens (NAcc) was identified as one of 5 regions that were activated by 5-HTDRN stimulation. We then employed an array of molecular genetic tools in transgenic mice to show that 5-HTDRN inputs to NAcc dynorphin neurons drive social avoidance in male mice after CIE by activating 5-HT2C receptors. NAcc dynorphin neurons also inhibit dopamine release during social interaction, reducing the motivational drive to engage with social partners. This study reveals that excessive serotonergic drive after chronic alcohol can promote social aversion by inhibiting accumbal dopamine release. Drugs that boost brain serotonin levels may be contraindicated for individuals with AUD.

neuroscience↗

bioRxiv2022

Tau pathology in the dorsal raphe may be a prodromal indicator of Alzheimer's disease

Protein aggregation in brainstem nuclei is thought to occur in the early stages of Alzheimers disease (AD), but its specific role in driving prodromal symptoms and disease progression is largely unknown. The dorsal raphe nucleus (DRN) contains a large population of serotonin (5-hydroxytryptamine; 5-HT) neurons that regulate mood, reward-related behavior, and sleep, which are all disrupted in AD. We report here that tau pathology is present in the DRN of individuals 54-80 years old without a known history of dementia and was found at higher frequency than -synuclein and TDP-43. Most AD cases had tau pathology in the DRN (90%), whereas only a subset contained TDP-43 or -synuclein, but not both (30%). To evaluate how early tau pathology impacts behavior, we overexpressed human P301L-tau in the DRN of mice and observed depressive-like behaviors and hyperactivity without any deficits in spatial memory. Tau pathology was predominantly found in neurons relative to glia and colocalized with a significant proportion of Tph2-expressing neurons in the DRN. 5-HT neurons were also hyperexcitable in P301L-tauDRN mice, and there was an increase in the amplitude of excitatory post-synaptic currents (EPSCs), suggestive of increased glutamatergic transmission. Moreover, astrocytic density was elevated in the DRN and accompanied by an increase in IL-1 and Frk expression, which is indicative of inflammation. Additionally, tau pathology was detected in axonal processes in the thalamus, hypothalamus, amygdala, and caudate putamen and a significant proportion of this tau pathology colocalized with the serotonin reuptake transporter (SERT), suggesting that tau may spread in an anterograde manner to regions outside the DRN. Together these results indicate that tau pathology accumulates in the DRN in a subset of individuals over 50 years and may lead to behavioral dysregulation, 5-HT neuronal dysfunction, and activation of local astrocytes which may be prodromal indicators of AD.

neuroscience↗

bioRxiv2022

Behavioral dysregulation and monoaminergic deficits precede memory impairments in human tau-overexpressing (htau) mice

Alzheimers disease (AD) poses an ever-increasing public health concern as the population ages, affecting more than 6 million Americans. AD patients present with mood and sleep changes in the prodromal stages that may be partly driven by loss of monoaminergic neurons in brainstem, but a causal relationship has not been firmly established. The goal of the present study was to evaluate depressive and anxiety-like behaviors in a mouse model of human tauopathy (htau mice) at 4 and 6 months of age prior to the onset of cognitive impairments and correlate these behavior changes with tau pathology, neuroinflammation, and monoaminergic dysregulation in the DRN and LC. We observed depressive-like behaviors at 4 months of age in male and female htau mice and hyperlocomotion in male htau mice. At 6 months, male htau mice developed anxiety-like behavior in the EZM, whereas hyperlocomotion had resolved by this time point. Depressive-like behaviors in the social interaction test persisted at 6 months but were resolved in the sucrose preference test. There was also a significant reduction in number and density of 5-HT-immunoreactive neurons in the rostral DRN in htau mice at 4 months and 5-HT neuronal density was negatively correlated with the intensity of phosphorylated tau staining in this subregion. Additionally, we found evidence of microglial activation in the mid and caudal DRN and astrocytic activation in the rostral DRN. 5-HT neuronal activity was reduced in the DRN and accompanied by downregulation of Tph2 and Sert, whereas genes that promote neuroinflammation and tau phosphorylation were upregulated. Finally, there was enhanced ptau202/205 staining and microglial activity in the LC of htau mice and reduced TH optical density, although the number and density of TH+ neurons were not altered. In total, these results suggest that tau pathology in the DRN and the resulting loss of serotonergic neurotransmission may drive depressive-like behaviors in the early stages of AD, whereas anxiety-like behaviors develop later and may result from neurodegeneration in other regions.

animal behavior and cognition↗

bioRxiv2022

Repeated ethanol exposure and withdrawal alters ACE2 expression in discrete brain regions: Implications for SARS-CoV-2 infection

Emerging evidence suggests that people with alcohol use disorders are at higher risk for SARS-CoV-2. SARS-CoV-2 engages angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) receptors for cellular entry. While ACE2 and TMPRSS2 genes are upregulated in the cortex of alcohol-dependent individuals, information on expression in specific brain regions and neural populations implicated in SARS-CoV-2 neuroinvasion, particularly monoaminergic neurons, is limited. We sought to clarify how chronic alcohol exposure affects ACE2 and TMPRSS2 expression in monoaminergic brainstem circuits and other putative SARS-CoV-2 entry points. C57BL/6J mice were exposed to chronic intermittent ethanol (CIE) vapor for 4 weeks and brains were examined using immunofluorescence. We observed increased ACE2 levels in the olfactory bulb and hypothalamus following CIE, which are known to mediate SARS-CoV-2 neuroinvasion. Total ACE2 immunoreactivity was also elevated in the raphe magnus (RMG), raphe obscurus (ROB), and locus coeruleus (LC), while in the dorsal raphe nucleus (DRN), ROB, and LC we observed increased colocalization of ACE2 with monoaminergic neurons. ACE2 also increased in the periaqueductal gray (PAG) and decreased in the amygdala. Whereas ACE2 was detected in most brain regions, TMPRSS2 was only detected in the olfactory bulb and DRN but was not significantly altered after CIE. Our results suggest that previous alcohol exposure may increase the risk of SARS-CoV-2 neuroinvasion and render brain circuits involved in cardiovascular and respiratory function as well as emotional processing more vulnerable to infection, making adverse outcomes more likely. Additional studies are needed to define a direct link between alcohol use and COVID-19 infection.

neuroscience↗