Biology subjects

Darvas, M.

Publications and source records attributed to Darvas, M..

8 recordsLinked to original sources

bioRxiv2026

Genetic Identification of Dopamine Neurons Required for Circadian Food Anticipatory Activity in Mice

Anticipating daily food availability is a conserved circadian behavior that persists even in animals lacking the suprachiasmatic nucleus, yet its neural substrates remain poorly defined. Previous studies implicated dopamine signaling in food anticipatory activity (FAA) but lacked the resolution to identify the responsible neuronal population. Here, we conditionally deleted tyrosine hydroxylase (Th) from molecularly defined dopamine neuron populations in mice. Broad deletion of Th in dopamine transporter-expressing neurons nearly abolished FAA, whereas restoration of Th in substantia nigra dopamine neurons rescued anticipatory locomotion. Surprisingly, deletion of Th from several large dopamine neuron populations had little effect on FAA. In contrast, deletion using Calb1Cre, targeting only [~]25% of substantia nigra dopamine neurons, produced a profound FAA deficit. Notably, these mice exhibited a profound loss of anticipatory locomotion while retaining substantial anticipatory food-seeking behavior. These findings identify a small Calbindin1+ dopamine population required for anticipatory locomotion and demonstrate that distinct behavioral components of food anticipation can be genetically dissociated.

neuroscience↗

bioRxiv2025

Kat5 cKO Biological Domain Signatures Align with Human Alzheimer Disease

BACKGROUNDAlzheimers disease (AD) is associated with amyloid plaques and can be caused by autosomal dominant mutations in APP or PSEN1/2, which form an enzyme substrate complex. Decreases in catalysis of AD mutant APP and PSEN1 supports the hypothesis that membrane delimitation of KAT5 could contribute to AD. METHODSWe compare the hippocampal transcriptome profiles of the Kat5 brain-specific knockout mouse to multiple AD datasets through alignment with the TREAT-AD AD biological domains. We examine KAT5 subcellular localization in human WT and AD neurons. RESULTSThe Kat5 KO mouse demonstrates downregulation of synaptic genes, metabolic pathways, and upregulation of DNA replication and repair, cell cycle and immune response genes. We see similar profiles in Kat5 and comparative AD datasets. KAT5 is restricted to the cytosol in human AD neurons. DISCUSSIONThis analysis supports the hypothesis that KAT5 nuclear signaling down stream of APP cleavage plays a pivotal role in neuronal homeostasis and immune regulation.

neuroscience↗

bioRxiv2025

An increased excitation and inhibition onto CA1 pyramidal cells sets the path to Alzheimer s disease

Synapses are critical targets of Alzheimers disease (AD), a highly prevalent neurodegenerative disease associated with accumulation of extracellular amyloid-{beta} peptides. Although amyloidosis and aggregation of the 42-amino acid amyloid-{beta} (A{beta}42) have long been considered pathogenic triggers for AD, clinical evidence linking high levels of A{beta}42 with normal cognition challenges this hypothesis. To resolve this conundrum on the role of A{beta}42 in regulating synaptic activity, we used an adeno-associated viral vector approach that triggers extracellular accumulation of A{beta}42 and spatial memory impairment. We show that A{beta}42 leads to an early increase in excitatory and proximal inhibitory synaptic transmission onto hippocampal CA1 pyramidal cells, and an increased expression of the glutamate transporter GLT-1 in these cells. A{beta}42 accumulation does not cause early cognitive deficits unless accompanied by an increased neuronal GLT-1 expression, suggesting this transporter is a critical mediator of A{beta}42s effects. These findings unveil key molecular and cellular mechanisms implicated with AD pathogenesis.

neuroscience↗

bioRxiv2024

A drug cocktail of rapamycin, acarbose, and phenylbutyrate enhances resilience to features of early-stage Alzheimer's disease in aging mice

The process of aging is defined by the breakdown of critical maintenance pathways leading to an accumulation of damage and its associated phenotypes. Aging affects many systems and is considered the greatest risk factor for a number of diseases. Therefore, interventions aimed at establishing resilience to aging should delay or prevent the onset of age-related diseases. Recent studies have shown a three-drug cocktail consisting of rapamycin, acarbose, and phenylbutyrate delayed the onset of physical, cognitive, and biological aging phenotypes in old mice. To test the ability of this drug cocktail to impact Alzheimers disease (AD), an adeno-associated-viral vector model of AD was created. Mice were fed the drug cocktail 2 months prior to injection and allowed 3 months for phenotypic development. Cognitive phenotypes were evaluated through a spatial navigation learning task. To quantify neuropathology, immunohistochemistry was performed for AD proteins and pathways of aging. Results suggested the drug cocktail was able to increase resilience to cognitive impairment, inflammation, and AD protein aggregation while enhancing autophagy and synaptic integrity, preferentially in female cohorts. In conclusion, female mice were more susceptible to the development of early stage AD neuropathology and learning impairment, and more responsive to treatment with the drug cocktail in comparison to male mice. Translationally, a model of AD where females are more susceptible would have greater value as women have a greater burden and incidence of disease compared to men. These findings validate past results and provide the rationale for further investigations into enhancing resilience to early-stage AD by enhancing resilience to aging.

pathology↗

bioRxiv2023

Behavioral and neuropathological features of Alzheimer's disease are attenuated in 5xFAD mice treated with intranasal GHK peptide

Efforts to find disease modifying treatments for Alzheimers disease (AD) have met with limited success in part because the focus has been on testing drugs that target a specific pathogenic mechanism. Multiple pathways have been implicated in the pathogenesis of AD. Hence, the probability of more effective treatment for AD is likely increased by using an intervention that targets more than one pathway. The naturally occurring peptide GHK (glycyl-L-histidyl-L-lysine), as a GHK-Cu complex, supports angiogenesis, remodeling, and tissue repair, has anti-inflammatory and antioxidant properties, and has been shown to improve cognitive performance in aging mice. In order to test GHK-Cu as a neurotherapeutic for AD, male and female 5xFAD transgenic mice on the C57BL/6 background at 4 months of age were given 15 mg/kg GHK-Cu intranasally 3 times per week for 3 months until 7 months of age. Results showed that intranasal GHK-Cu treatment delayed cognitive impairment, reduced amyloid plaques, and lowered inflammation levels in the frontal cortex and hippocampus. These observations suggest additional studies are warranted to investigate the potential of GHK-Cu peptide as a promising treatment for AD.

neuroscience↗

bioRxiv2023

The neurons that drive infradian sleep-wake and mania-like behavioral rhythms

Infradian mood and sleep-wake rhythms with periods of 48 hr and beyond have been observed in bipolar disorder (BD) subjects that even persist in time isolation, indicating an endogenous origin. Here we show that mice exposed to methamphetamine (Meth) in drinking water develop infradian locomotor rhythms with periods of 48 hr and beyond which extend to sleep length and mania-like behaviors in support of a model for cycling in BD. This cycling capacity is abrogated upon genetic disruption of DA production in DA neurons of the ventral tegmental area (VTA) or ablation of nucleus accumbens (NAc) projecting, dopamine (DA) neurons. Chemogenetic activation of NAc-projecting DA neurons leads to locomotor period lengthening in clock deficient mice, while cytosolic calcium in DA processes of the NAc was found fluctuating synchronously with locomotor behavior. Together, our findings argue that BD cycling relies on infradian rhythm generation that depends on NAc-projecting DA neurons.

neuroscience↗

bioRxiv2023

Integrated multimodal cell atlas of Alzheimer's disease

Alzheimers disease (AD) is the most common cause of dementia in older adults. Neuropathological and imaging studies have demonstrated a progressive and stereotyped accumulation of protein aggregates, but the underlying molecular and cellular mechanisms driving AD progression and vulnerable cell populations affected by disease remain coarsely understood. The current study harnesses single cell and spatial genomics tools and knowledge from the BRAIN Initiative Cell Census Network to understand the impact of disease progression on middle temporal gyrus cell types. We used image-based quantitative neuropathology to place 84 donors spanning the spectrum of AD pathology along a continuous disease pseudoprogression score and multiomic technologies to profile single nuclei from each donor, mapping their transcriptomes, epigenomes, and spatial coordinates to a common cell type reference with unprecedented resolution. Pseudo-progression analysis showed two major epochs corresponding with a slow early increase in pathology and a later exponential increase that correlated with cognitive decline. The early phase included inflammatory microglial and reactive astrocyte component, as well as a selective loss of Sst+ inhibitory neuron types in superficial cortical layers, loss of myelinating oligodendrocytes, and up-regulation of a re-myelination program by OPCs. The later phase involved loss of excitatory neurons and Pvalb and Vip neuron subtypes also predominantly in superficial layers. These cell vulnerabilities were also seen in prefrontal cortex and replicated by other independent studies when integrated with the BRAIN Initiative reference. Study data and exploratory tools are freely available to accelerate progress in AD research at SEA-AD.org.

genomics↗

bioRxiv2018

A diversity of transcriptional responses to reduced dopamine in SNc and VTA in a mouse Tyrosine hydroxylase KO model of Parkinson’s Disease

Parkinsons Disease (PD), is a neurodegenerative disorder affecting both cognitive and motor functions. It is characterized by decreased brain dopamine (DA) and a selective and progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNc), whereas dopaminergic neurons in the ventral tegmental area (VTA) show reduced vulnerability. The majority of animal models of PD are genetic lesion or neurotoxin exposure models that lead to death of dopaminergic neurons. Here we use a DAT:TH KO mouse model that by inactivation of the tyrosine hydroxylase (Th) gene in dopamine transporter-expressing neurons, causes selective depletion of striatal dopamine without affecting DA neuron survival. We analyzed transcriptome responses to decreased DA in both pre- and post-synaptic dopaminergic brain regions of DAT:TH KO animals. We detected only few differentially expressed genes in the post-synaptic regions as a function of DA deficiency. This suggests that the broad striatal transcriptional changes in neurodegeneration-based PD models are not direct effects of DA depletion, but are rather a result of DA neuronal death. However, we find a number of dopaminergic genes differentially expressed in SNc, and to a lesser extent in VTA, as a function of DA deficiency, providing evidence for a DA-dependent feedback loop. Of particular interest, expression of Nr4a2, a crucial transcription factor maintaining DA neuron identity, is significantly decreased in SNc, but not VTA, of DAT:TH KO mice, implying a potential protective role for DA in the SNc.

neuroscience↗