Fragile X syndrome is a leading cause of intellectual disability and autism spectrum disorder, for which therapies are limited. A mouse model of fragile X syndrome, the Fmr1 knock-out (KO) mouse, has been particularly valuable for interrogating the molecular, cellular, and circuit mechanisms that underlie the neurological deficits seen in this syndrome. Key deficits in fragile X syndrome include impairments in social behaviors, cognition, and motor learning. Given the difficulties in extrapolating complex human behaviors to mouse models, motor behaviors are a particularly tractable form of learning to study in the mouse. We investigated a form of forelimb reach learning in both male and female Fmr1 KO mice, quantifying different parameters of the task using both manual analysis and DeepLabCut-based tracking of reach trajectories. While Fmr1 KO mice show impaired learning overall, our results showed that the presence or absence of a cue that signals reward alleviated some of the deficits. In addition to a s...

Epigenetic and transcriptional mechanisms are key contributors to alcohol use disorder (AUD). However, a better understanding of the specific genes, transcripts, and chromatin marks affected is necessary to inform novel pharmacotherapies. Here, we systematically investigate the genome-wide epigenetic and transcriptomic effects of ethanol across key brain regions relevant to AUD and assess how these outcomes differ between acute and chronic exposure in male C57BL/6J mice. We show that alcohol-derived acetate contributes to histone acetylation in the brain in response to acute or chronic exposure, with a broader and more robust effect following repeated exposure. Further, we find that chromatin and transcriptomic changes elicited by acute or chronic ethanol exposure are predominantly specific to brain region and observe more robust dysregulation of gene and transcript expression following acute exposure. We show that ethanol-induced transcriptional changes are paradigm dependent in some brain regions, most s...

Echolocation enables blind individuals to perceive and navigate their environment by emitting clicks and interpreting their returning echoes. While expert blind echolocators demonstrate remarkable spatial accuracy, the behavioral and neural mechanisms by which spatial echoacoustic cues are combined across repeated samples remain less explored. Here, we investigated the temporal dynamics of spatial information processing in human click-based echolocation using electroencephalography (EEG). Blind expert echolocators ( n  = 4, all males) and novice sighted participants ( n  = 21, 12 males) localized virtual spatialized echoes derived from realistic synthesized mouth clicks, presented in trains of 2–11 clicks. Behavioral results showed that blind expert echolocators significantly outperformed sighted controls in spatial localization. For these experts, localization thresholds decreased as the number of clicks increased, a pattern consistent with cumulative integration of spatial information across repeated sam...

Trafficking of intracellular cargoes along the neuronal axonal microtubule tracks is a motor protein-dependent process. Here, we use a targeted genetic approach to knock down candidate kinesin genes involved in trafficking organelles in male and female Drosophila melanogaster . Live imaging experiments revealed intracellular trafficking changes, and kinesins 1 and 3 were identified as critical regulators. Disruptions in either gene product reduce rates of axonal trafficking in motor neurons (MNs) and lead to the formation of large intracellular aggregates. Kinesin disruptions led to significant changes in neuropeptide (NP) abundance at boutons and changes in synaptic morphology. Confocal imaging revealed fewer NPs trafficking through or getting captured by synapses in kinesin knockdown experiments and a dramatic reduction in NP release at MN terminals. A profound reduction in neuromuscular transduction and excitation–contraction coupling in kinesin 1 knockdowns, but not for kinesin 3, was observed. Collect...

Age-related alterations in myelin are a prominent feature of brain aging, yet how myelin-associated markers and oligodendrocyte lineage cell populations change across the primate lifespan remains incompletely characterized. Here, we provide a multimodal, cross-sectional analysis of myelin-related imaging and cellular markers in the prefrontal cortex (PFC) of age-matched both male and female rhesus macaques across postnatal development and aging using a multimodal approach combining magnetic resonance imaging (MRI), histological analysis, immunohistochemistry, and RNAscope in situ hybridization. We quantified regional gray and white matter volumes and myelin water fraction measures in prefrontal cortex (PFC) subregions BA9 and BA46 across four age groups: 5, 10, 15, and 30 years. Myelin water fraction and regional brain volumes exhibited age-dependent increases from childhood through adolescence, peaking at 15 years, followed by a decline in aged animals. Histological analyses revealed age-associated change...

Ras-related C3 botulinum toxin substrate 1 (Rac1) is a small GTPase that regulates actin cytoskeleton dynamics and synaptic plasticity. Rac1 has been implicated in active forgetting, but whether it also constrains the consolidation of new memories remains unclear. Here we show that systemic administration of the Rac1 inhibitor 1A-116 after training in the novel object recognition task markedly extends memory persistence in rats. A single post-training injection of 1A-116 enhanced recognition memory for at least 28 d without altering locomotor- or anxiety-related behaviors. When given after a brief, subthreshold training session that normally supports only short-term memory, 1A-116 enabled long-term retention that required hippocampal protein synthesis. This promnesic effect was time-dependent, independent of sex, and consistent with Rac1 acting as a negative regulator of memory consolidation rather than merely promoting forgetting. These findings indicate that Rac1 activity after learning limits the consol...

Bipolar cells relay visual signals from photoreceptors to ganglion cells. In the mouse retina, 15 bipolar cell subtypes have been identified and are classified as ON or OFF bipolar cells based on their responses to light or as rod or cone bipolar cells based on their photoreceptor connectivity. Despite this diversity, the distinct structural and functional roles of bipolar cell subtypes in visual information processing remain poorly understood, largely due to lack of tools and models for their characterization. In this study, we generated inducible Cre mouse lines driven by the promoters of Vsx1 , Lhx3 , and Lhx4 and crossed them with ChR2EYFP reporter mice to trace lineage and characterize bipolar cell subtypes in postnatal and adult mouse retinas. Following tamoxifen induction in adult male and female mice, ChR2EYFP expression was detected in type 2, 6, and 7 bipolar cells in the Vsx1 CreERT2 line; type 1b, 2, and 6 bipolar cells in the Lhx3 CreERT2 line; and type 2, 3, 4, and 5 bipolar cells in the Lhx4...

Environmental enrichment (EE) reduces vulnerability to multiple drugs of abuse, yet its impact on fentanyl use and relapse-like behavior remains unclear. Here, we tested whether long-term, nonsocial, object-based EE alters fentanyl self-administration, extinction, and stress-induced reinstatement in male and female rats. Rats were individually housed in either standard nonenriched (NE) conditions or in EE cages containing a rotating set of novel objects beginning at least 3 d prior to self-administration. EE did not impact acquisition of fentanyl self-administration but reduced fentanyl intake during maintenance of self-administration and reduced the persistence of drug-seeking in extinction. Following extinction, yohimbine robustly reinstated drug-seeking behavior in NE rats but reinstatement in EE rats was markedly attenuated, indicating reduced sensitivity to stress-induced relapse triggers. Circulating corticosterone levels were lower in EE rats across the experiment and were positively correlated with...

We lack a mechanistic understanding of how cortical contributions to balance control change in aging and Parkinson's disease (PD). Balance is governed by brainstem circuits, with higher-order centers like the cortex or basal ganglia becoming engaged as challenge increases or balance health declines. We previously showed that parallel sensorimotor feedback loops engaging brainstem and cortical circuitry contribute to muscle activity for balance control in young adults (YAs). Here, we analyze data from male and female older adults (OAs) with and without PD, decomposing perturbation-evoked tibialis anterior and medial gastrocnemius muscle activity into hierarchical components based on latencies of feedback control loops. We found that balance-correcting muscle activity followed a stereotypical waveform of long-latency responses (LLRs): LLR1 began ∼120 ms and LLR2 occurred ∼210 ms, respectively, consistent with subcortical and cortical feedback latencies. Both LLRs increased with balance challenge and could be...

Stressful events are a leading factor in the development of depression. The medial prefrontal cortex (mPFC) is strongly associated with depression etiology and exposure to uncontrollable stressors results in synaptic dysfunction and loss. Learned helplessness is a behavioral paradigm that measures effects of repeated exposure to uncontrollable, inescapable stress on later responses to escapable stress. We therefore performed a proteomic analysis of mPFC synaptosomes in a mouse learned helplessness model to identify molecular changes that could contribute to functional consequences of inescapable stress. Male and female mice were evaluated at baseline and following exposure to escapable or inescapable stress followed by an active avoidance test. Label-free mass spectrometry followed by pathway and protein–protein interaction network analyses identified alterations in signaling pathways involved in energy metabolism, neurotransmitter signaling, and protein shuttling. Furthermore, phosphoproteomics revealed a...