Biology subjects

Stackman, R. W.

Publications and source records attributed to Stackman, R. W..

3 recordsLinked to original sources

bioRxiv2026

Ligand-Specific Effects of 5-HT2A Receptor Antagonists on Fear Extinction in C57BL/6J Mice: Comparative insights from MDL 11,939 and MDL 100,907

Serotonin (5-HT) 2A receptors (5-HT2AR) modulate corticolimbic circuits regulating fear extinction. Although activation of these receptors has been shown to facilitate fear extinction, the behavioral consequences of 5-HT2AR antagonism during extinction is not well defined. Here, we examined the systemic effects of two 5-HT2A receptor antagonists, the mixed 5-HT2A/2C antagonist MDL 11,939 (Glemanserin) and the selective 5-HT2A antagonist MDL 100,907 (Volinanserin) on fear extinction in adult C57BL/6J mice. Prior to drug administration, mice assigned to future treatment groups acquired comparable conditioned freezing responses during delay fear conditioning. Twenty-four hours later, acute administration of MDL 11,939 (1.0 mg/kg) or MDL 100,907 (0.01 mg/kg) increased freezing to the first conditioned stimulus (CS) presentation on Extinction Day 1, indicating enhanced expression of conditioned fear. However, acquisition of fear extinction differed between the respective cohorts of mice treated with the two 5-HT2AR antagonists. Repeated administration of MDL 11,939 significantly impaired extinction, as evidenced by increased freezing across extinction trials and an increased number of trials required to reach extinction criterion. In contrast, MDL 100,907 has reported affinity for did not significantly alter extinction under either acute or repeated dosing conditions. Because MDL 11,939 has reported affinity for 5-HT2C receptors, we tested potential contributions of 5-HT2C receptor antagonism in a separate cohort of mice using two doses of the selective 5-HT2C antagonist, SB 242084. Neither dose affected conditioned fear expression, extinction learning, or trials required to reach extinction criterion. Together, these findings demonstrate ligand-specific and dose-dependent effects of 5-HT2AR antagonism on fear extinction and suggest that distinct intracellular receptor signaling pathways may differentially regulate extinction-related behavior. HighlightsO_LIMDL 11,939 and MDL 100,907 differentially affect fear extinction behavior C_LIO_LIRepeated MDL 11,939 impairs extinction learning in C57BL/6J mice C_LIO_LIMDL 100,907 did not significantly alter extinction learning C_LIO_LISelective 5-HT2C antagonism does not influence extinction C_LIO_LILigand-dependent 5-HT2A signaling shapes extinction outcomes C_LI

neuroscience↗

bioRxiv2025

Generating the head direction signal: Two types of head direction cells in the lateral mammillary and dorsal tegmental nuclei.

Head direction (HD) cells discharge as a function of the animals directional heading and are believed to underlie ones sense of direction. They have been identified in several brain areas, although the signal is thought to be generated across the connections between the lateral mammillary (LMN) and dorsal tegmental nuclei (DTN). Computational models have proposed that a ring-attractor network underlies the mechanisms that generate the signal. These models usually contain separate populations of neurons that encode HD and angular head velocity (AHV). Currently, both cell types have been identified in the LMN and DTN. However, HD attractor models also require cells, referred to as rotation cells, which are sensitive to both parameters conjunctively (HD+AHV). Here we sought to identify such cells in the LMN-DTN network. We identified two distinct types of HD cells. The majority of LMN HD cells ([~]64%) were AHV-independent, responding only to the animals directional heading. However, a second population ([~]36%) was sensitive to both HD and AHV. Both symmetric and asymmetric AHV cell types were found. Similar results were found in the DTN, but with a higher percentage of conjunctive HD+AHV cells (60%). Notably, many HD+AHV conjunctive cells were also sensitive to the animals linear velocity (LV). In contrast, HD cells in the anterodorsal thalamus were rarely sensitive to AHV or LV. These findings demonstrate that the requisite rotation-type HD cell is present in brain areas responsible for generating the HD signal and supports the view that an attractor style network underlies its generation in mammals. Statements and DeclaratioThis manuscript does not represent the official view of the National Institute of Neurological Disorders and Stroke (USA) (NINDS), the National Institutes of Health (USA) (NIH), or any part of the US Federal Government. No official support or endorsement of this article by the NINDS or NIH is intended or should be inferred.

neuroscience↗

bioRxiv2025

Lack of ADAP1/Centaurin-α1 Ameliorates Cognitive Impairment and Neuropathological Hallmarks in a Mouse Model of Alzheimer's Disease

ArfGAP, with dual PH domain-containing protein 1/Centaurin-1 (ADAP1CentA1), is a brain-enriched and highly conserved Arf6 GTPase-activating and Ras-anchoring protein. ADAP1 is involved in dendritic outgrowth and arborization, synaptogenesis, and axonal polarization by regulating the dynamics of the actin cytoskeleton. An increased level of ADAP1 and its association with amyloid plaques in the human Alzheimers disease (AD) brain suggest a role for this protein in AD progression. To understand the role of ADAP1/CentA1 in neurodegeneration, we crossbred CentA1 KO mice with the hAPP-J20 mouse model of AD (J20 x CentA1 KO). We then evaluated the gene expression profile and the behavioral and neuropathological hallmarks of AD to determine the impact of eliminating ADAP1/CentA1 expression on AD-related phenotypes. Spatial memory assessed by the Morris Water Maze test showed significant impairment in J20 mice, which was rescued by the deletion of CentA1. Neuropathological hallmarks of AD, such as deposits of amyloid plaques and neuroinflammation, were significantly reduced in the AD model mice with CentA1 KO background. To identify potential mediators of AD phenotype rescue, we analyzed differentially expressed genes (DEGs) between genotypes, by employing transcriptome profiling with Nanostring nCounter Neuropathology and Neuroinflammation panels. We found significant upregulation of genes associated with apoptosis and gliosis in the brain of J20 mice. However, many of these genes, including the pro-apoptotic gene, Bid, were restored in the brains of J20 x CentA1 KO mice compared to J20 mice. In summary, our data indicate that CentA1 is required for the progression of AD phenotypes and that targeting CentA1 signaling at mitochondria might have therapeutic potential for AD prevention or treatment. SIGNIFICANCE STATEMENTADAP1/Centaurin-1 (CentA1) is highly enriched in the brain and increased CentA1 level has been linked to Alzheimers disease (AD). However, the precise role of ADAP1 in the pathogenesis of AD is poorly understood. We found that genetic deletion of CentA1 in the AD model mice rescues the pathological hallmarks of AD, including loss of dendritic spines in the hippocampus, amyloid plaque deposition, neuroinflammation and spatial memory deficits. Transcriptome analysis of forebrain samples using NanoString nCounter panels for 880 genes, identified the pro-apoptotic protein, Bid, with significantly reduced expression in the J20 mice on ADAP1 KO background. These findings point towards a role of ADAP1 in the activation of the mitochondrial pathways of death associated with the progression of neurodegeneration.

neuroscience↗