Biology subjects

Kelberman, M. A.

Publications and source records attributed to Kelberman, M. A..

8 recordsLinked to original sources

bioRxiv2026

Hypothalamic tauP301L pathology disrupts pair bonding in monogamous prairie voles

Although dementias primarily affect memory, they also disrupt our closest social relationships, resulting in elevated caregiver burden and worse patient outcomes. However, the mechanistic study of how pathology affects social attachments is limited by the use of laboratory rodents that do not form selective, long-term bonds. Here, in monogamous prairie voles, we expressed dementia-causing tauP301L in the paraventricular hypothalamus of 12- and 18-month-old animals, and separately, from birth through 18-months, across hippocampocortical regions. Hippocampocortical expression of tauP301L did not yield deficits in social or non-social dementia-related phenotypes. In contrast, tauP301L expressed in the hypothalamus yielded sex- and age-dependent social bonding deficits. 18-month males with hypothalamic tau pathology failed to form bonds and displayed blunted sociability, effects that converged across bonding assays. In addition, healthy 18-month males paired with a hypothalamic tau-expressing female also showed reduced partner preference, suggesting that pathology exerts vicarious effects on partners. Social behavior of both healthy females and those expressing tauP301L were unaffected. 18-month tauP301L males also showed elevated oxytocin fluorescence. These findings establish direct and vicarious disruptions to pair bonding induced by hypothalamic tau pathology in male prairie voles, potentially via altered oxytocin signaling.

neuroscience↗

bioRxiv2026

Hypothalamus amyloid levels are associated with early sex-dependent alterations in energy homeostasis in TgF344-AD rats

We reported previously that diet-induced obesity exacerbates early-stage Alzheimers disease (AD)-like pathology in TgF344-AD rats. Our findings also suggested that TgF344-AD rats may be prone to weight gain during early AD development, which we assessed here. Energy intake, body composition, and the impact of glucose administration on blood glucose were also assessed. Body temperature, intrascapular brown adipose tissue (iBAT) mass, and iBAT uncoupling protein-1 (UCP1) expression were used as indicators of thermogenic function. Soluble amyloid {beta}40 (A{beta}40) and A{beta}42 were quantified in hypothalamus. Male TgF344-AD rats began to outweigh wildtype (WT) littermates by 5 weeks of age; this increase emerged later in female TgF344-AD rats (~5 months). Female TgF344-AD rats ingested more energy from chow and a high fat, high sugar (HFHS) diet, gained more weight on the HFHS diet, and had lower UCP1 than WT rats, effects not observed in male TgF344-AD rats. Surprisingly, male and female TgF344-AD rats had increased body temperatures. This was restricted to the dark phase in females, which is when they ingest excess calories. Finally, the HFHS diet disrupted glucose regulation in male but not female TgF344-AD rats. These findings suggest that increases in energy intake and decreases in UCP1 may contribute to the additional weight gain in female TgF344-AD rats. The causes for these increases in males remain unclear. Hypothalamic A{beta}42 correlated with glucose dysregulation in male TgF344-AD rats and BAT mass in female TgF344-AD rats, raising the possibility that increases in A{beta}42 in hypothalamus produce sex-specific disruptions in energy homeostasis.

neuroscience↗

bioRxiv2025

Impact of early locus coeruleus lesions in the TgF344 Alzheimer's disease rat model

INTRODUCTIONIn murine models of Alzheimers disease (AD), lesioning the locus coeruleus-norepinephrine (LC-NE) system with DSP-4 exacerbates AD-like neuropathology and cognitive impairment. However, the impact of LC lesions during prodromal stages is poorly characterized. METHODSTgF344-AD and wild-type rats received monthly injections of DSP-4 or saline from 1-5 months of age, a time point preceding forebrain plaque or tangle deposition in TgF344-AD rats, after which behavior and pathology were assessed. RESULTSDSP-4 compromised LC cell bodies, fibers, and NE content. LC lesion and the AD transgene each affected several affective behaviors and/or cognition individually, but few interactions were found and DSP-4 failed to exacerbate behavioral phenotypes or neuropathology in TgF344-AD rats. DISCUSSIONCombined with previous literature, our data suggest that LC lesions exacerbate pre-existing AD-like pathology and behavioral impairments, rather than accelerate their onset. Further characterization of LC lesions in TgF344-AD rats at different ages is warranted. Research-in-ContextO_LISystemic review: The authors reviewed existing literature using traditional sources, including PubMed. Previous studies investigated the impact of locus coeruleus (LC) lesions on Alzheimers disease (AD)-like neuropathology and behavior in murine models of AD. However, the impact of LC degeneration in an animal model that expresses both amyloid and endogenous tau pathology at a time point before the emergence of significant forebrain pathology is underexplored. C_LIO_LIInterpretation: We expanded the behavioral and molecular characterization of TgF344-AD rats in response to N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride (DSP-4)-induced LC lesions during the pre-pathology stages of disease. Unexpectedly, we found that TgF344-AD genotype and DSP-4 rarely interacted to exacerbate AD-related symptoms or pathology. C_LIO_LIFuture Directions: Our results indicate LC lesions do not accelerate onset of AD-like neuropathology or behavioral impairment in this model. Future studies in older TgF344-AD animals and using different DSP-4 treatment regimens would help clarify the relationship between LC integrity and AD progression. C_LI HighlightsO_LILocus coeruleus damage causes apathy-like behavior and changes in arousal C_LIO_LITgF344-AD genotype induces social recognition deficits and anxiety-like behavior C_LIO_LILocus coeruleus damage and TgF344-AD genotype rarely interact to worsen deficits C_LIO_LIInteractions that exacerbate Alzheimers disease neuropathology were also scarce C_LI

neuroscience↗

bioRxiv2024

Diversity of ancestral brainstem noradrenergic neurons across species and multiple biological factors

The brainstem cell group, locus coeruleus (LC), is present across vertebrates and influences cardiorespiratory, metabolic, immune, and cognitive functions by activating in two putatively distinct firing patterns. Yet, the degree to which the LC firing rates and patterns are homogenous across species has never been assessed due to inherently limited sample sizes. To remedy this, we pooled cross-species data from 20 laboratories to show that firing rates differ across species and are modulated by sex, age, and type of in vitro or in vivo preparation. Contrary to the prevailing dual-mode firing pattern schema, we observed patterns spread across a low-dimensional manifold, with subregions enriched for specific biological factors and neurodegenerative disease models. Our findings show considerable diversity in an ancestral vertebrate neuromodulatory system.

neuroscience↗

bioRxiv2024

The Effects of Locus Coeruleus Optogenetic Stimulation on Global Spatiotemporal Patterns in Rats

Whole-brain intrinsic activity as detected by resting-state fMRI can be summarized by three primary spatiotemporal patterns. These patterns have been shown to change with different brain states, especially arousal. The noradrenergic locus coeruleus (LC) is a key node in arousal circuits and has extensive projections throughout the brain, giving it neuromodulatory influence over the coordinated activity of structurally separated regions. In this study, we used optogenetic-fMRI in rats to investigate the impact of LC stimulation on the global signal and three primary spatiotemporal patterns. We report small, spatially specific changes in global signal distribution as a result of tonic LC stimulation, as well as regional changes in spatiotemporal patterns of activity at 5 Hz tonic and 15 Hz phasic stimulation. We also found that LC stimulation had little to no effect on the spatiotemporal patterns detected by complex principal component analysis. These results show that the effects of LC activity on the BOLD signal in rats may be small and regionally concentrated, as opposed to widespread and globally acting.

neuroscience↗

bioRxiv2024

Aging leads to sex-dependent effects on pair bonding and increased number of oxytocin-producing neurons in monogamous prairie voles

Pair bonds powerfully modulate health, which becomes particularly important when facing the detrimental effects of aging. To examine the impact of aging on relationship formation and response to loss, we examined behavior in 6-, 12-, and 18-month male and female prairie voles, a monogamous species that forms mating-based pair bonds. We found that older males (18-months) bonded quicker than younger voles, while similarly aged female voles increased partner directed affiliative behaviors. Supporting sex differences in bonding behaviors, we found that males were more likely to sample both partner and novel voles while females were more likely to display partner preference during the initial 20 minutes of the test. Using partner separation to study loss, we observed an erosion of partner preference only in 12-month females, but an overall decrease in partner-directed affiliation in females across all groups, but not in males. Finally, we found that the number of oxytocin, but not vasopressin, cells in the paraventricular hypothalamus increased during aging. These results establish prairie voles as a novel model to study the effects of normal and abnormal aging on pair bonding. HighlightsO_LI18-month male voles demonstrate accelerated bond formation C_LIO_LI18-month female voles increase partner-directed huddling after 2 wks C_LIO_LIBonds erode faster in 12-month female voles after partner separation C_LIO_LIFemale behavior from partner preference tests is reflected in free interaction C_LIO_LIThe number of paraventricular hypothalamus oxytocin cells increase during aging C_LI

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bioRxiv2022

The Neurotoxin DSP-4 Dysregulates the Locus Coeruleus-Norepinephrine System and Recapitulates Molecular and Behavioral Aspects of Prodromal Neurodegenerative Disease

The noradrenergic locus coeruleus (LC) is among the earliest sites of tau and alpha-synuclein pathology in Alzheimers disease (AD) and Parkinsons disease (PD), respectively. The onset of these pathologies coincides with loss of noradrenergic fibers in LC target regions and the emergence of prodromal symptoms including sleep disturbances and anxiety. Paradoxically, these prodromal symptoms are indicative of a noradrenergic hyperactivity phenotype, rather than the predicted loss of norepinephrine (NE) transmission following LC damage, suggesting the engagement of complex compensatory mechanisms. Because current therapeutic efforts are targeting early disease, interest in the LC has grown, and it is critical to identify the links between pathology and dysfunction. We employed the LC-specific neurotoxin DSP-4, which preferentially damages LC axons, to model early changes in the LC-NE system pertinent to AD and PD in male and female mice. DSP-4 (2 doses of 50 mg/kg, 1 week apart) induced LC axon degeneration, triggered neuroinflammation and oxidative stress, and reduced tissue NE levels. There was no LC cell death or changes to LC firing, but transcriptomics revealed reduced expression of genes that define noradrenergic identity and other changes relevant to neurodegenerative disease. Despite the dramatic loss of LC fibers, NE turnover and signaling were elevated in terminal regions and were associated with anxiogenic phenotypes in multiple behavioral tests. These results represent a comprehensive analysis of how the LC-NE system responds to axon/terminal damage reminiscent of early AD and PD at the molecular, cellular, systems, and behavioral levels, and provides potential mechanisms underlying prodromal neuropsychiatric symptoms.

neuroscience↗

bioRxiv2021

Consequences of endogenous and virally-induced hyperphosphorylated tau on behavior and cognition in a rat model of Alzheimer's disease

BackgroundThe locus coeruleus (LC) is one of the earliest brain regions to accumulate hyperphosphorylated tau, but a lack of animal models that recapitulate this pathology has hampered our ability to understand its contributions to the pathophysiology of Alzheimers disease (AD). ObjectiveWe previously reported that TgF344-AD rats, which overexpress mutant human amyloid precursor protein and presenilin-1, accumulate early endogenous hyperphosphorylated tau in the LC. Here, we used TgF344-AD rats and a wild-type (WT) human tau virus to interrogate the effects of endogenous hyperphosphorylated rat tau and human tau in the LC on AD-related neuropathology and behavior. MethodsTwo-month old TgF344-AD and WT rats received bilateral LC infusions of WT human tau or mCherry control virus driven by the noradrenergic-specific PRSx8 promoter. Rats were subsequently assessed at 6 and 12 months for arousal (sleep latency), anxiety-like behavior (open field, elevated plus maze, novelty-suppressed feeding), passive coping (forced swim task), and learning and memory (Morris water maze and fear conditioning). Hippocampal microglia, astrocyte, and AD pathology were evaluated using immunohistochemistry. ResultsIn general, the effects of age were more pronounced than genotype or treatment; older rats displayed greater hippocampal pathology, took longer to fall asleep, had reduced locomotor activity, floated more, and had impaired cognition compared to younger animals. TgF344-AD rats showed increased anxiety-like behavior and impaired learning and memory. The tau virus had negligible influence on most measures. ConclusionEffects of hyperphosphorylated tau on AD-like neuropathology and behavioral symptoms were subtle. Further investigation of different forms of tau is warranted.

neuroscience↗