The nucleus accumbens (NAc) is a critical component of a limbic basal ganglia circuit that is thought to play an important role in decision-making and the processing of rewarding stimuli. As part of this circuit, dopamine D1 receptor-expressing medium spiny neurons (D1-MSNs) of the NAc core are known to send a major projection to the substantia nigra pars reticulata (SNr). However, the functional role of this SNr-projecting NAc D1-MSNs (NAcD1-MSN-SNr) pathway is still largely uncharacterized. Moreover, as the SNr is thought to belong to both limbic and motor information processing basal ganglia loops, it is possible that the NAcD1-MSN-SNr pathway may be able to influence both limbic and motor functions. In this study we investigated the effect of optogenetic manipulation of the NAcD1-MSN-SNr pathway on reward-learning and locomotor behavior in male mice. Stimulation of the axon terminals of NAc core D1-MSNs in the SNr induced a preference for a laser-paired location, self-stimulation via a laser-paired lev...

Studies of voluntary visual-spatial attention have used attention-directing cues, such as arrows, to induce or instruct observers to focus selective attention on relevant locations in visual space in order to detect or discriminate subsequent target stimuli. In everyday vision, however, voluntary attention is influenced by a host of factors, most of which are quite different from the laboratory paradigms that utilize attention-directing cues. These factors include priming, experience, reward, meaning, motivations, and high-level behavioral goals. Attention that is endogenously directed in the absence of external attention-directing cues has been referred to as self-initiated attention, or as in our prior work, as “willed attention” where volunteers decide where to attend in respond to a prompt to do so. Here, we used a novel paradigm that eliminated external influences (i.e., attention-directing cues and prompts) about where and/or when spatial attention should be directed. Using machine learning decoding ...

The cochlea hair cells transform mechanic sounds to neural signals with a remarkable sensitivity and resolution. This is achieved via the precisely sculpted mechanotransduction apparatus of the hair cells and the supporting structure of the cochlea. The shaping of the mechanotransduction apparatus, the staircased stereocilia bundles on the apical surface of the hair cells, requires an intricate regulatory network including planar cell polarity and primary cilia genes in orienting stereocilia bundles and the building molecular machinery of the apical protrusions. The mechanism linking these regulatory components is unknown. Here we show that a small GTPase known for its role in protein trafficking, Rab11a, is required for ciliogenesis in hair cells during development in mice. In addition, in the absence of Rab11a, stereocilia bundles lost their cohesion and integrity, and mice are deaf. These data indicate an essential role of protein trafficking in the formation of hair cell mechanotransduction apparatus, ...

Despite the significant health consequences of anxiety, the neural basis of regulation for personal anxious events is not well understood. We compared brain activity and functional connectivity during cognitive emotion regulation strategies (reappraisal and acceptance) for personal anxious events. Functional MRI data were obtained while 35 college students were thinking about (the control condition), reappraising, or accepting their own anxiety-provoking situations. Although reappraisal and acceptance decreased anxiety, no statistically significant differences were observed in the brain activation levels between cognitive emotion regulation strategies and the control condition. However, acceptance decreased activation in the posterior cingulate cortex and precuneus more than reappraisal. Moreover, functional connectivity with the amygdala and ventral anterior insula distinguished the emotion regulation strategies for anxiety. Reappraisal showed stronger negative functional connectivity with the amygdala an...

Approximately 10% of births are preterm (PTB; <37 weeks gestational age; GA), which confers risk for cognitive, behavioral, and mental health challenges. Using the large and relatively diverse (i.e., designed to reflect sociodemographic variation in the US population) Adolescent Brain Cognitive DevelopmentSM Study (ABCD Study®), we characterized the impact of PTB on brain structure in middle-late childhood (9-10 years). The ABCD sample covers the GA spectrum, and the large sample size (∼11,500) permits consideration of how associations between PTB and brain structure are impacted by GA, sex, birthweight, and analytic choices such as controlling for total brain size. We found a pattern of relative cortical thinning in temporoparietal and dorsal prefrontal regions and thickening of medial prefrontal and occipital regions in PTB compared to children born full term (≥37 weeks GA). This pattern was apparent when controlling for mean thickness and when considering moderate (>32 and <37 weeks GA) and very PTB (≤3...

Gentle stroking of the skin is a common social touch behavior with positive affective consequences. A preference for slow versus fast stroking of hairy skin has been closely linked to the firing of unmyelinated C-tactile (CT) somatosensory afferents. Because the firing of CT afferents strongly correlates with touch pleasantness, the CT pathway has been considered a social-affective sensory pathway. Recently, ablation of the spinothalamic pathway- thought to convey all C-fiber sensations- in patients with cancer pain impaired pain, temperature, and itch, but not ratings of pleasant touch. This suggested integration of afferent A and CT fiber input in the spinal cord, or mechanoreceptive A-fiber contributions to computations of touch pleasantness in the brain. However, contribution of mechanoreceptive A-fibers to touch pleasantness- in humans without pain- remains unknown. In the current, single-blinded study we performed two types of peripheral nerve blocks in healthy adults to temporarily eliminate the con...

Animals are capable of representing different scale spaces from smaller to larger ones. However, most laboratory animals live their life in a narrow range of scale spaces like home-cages and experimental setups, making it hard to extrapolate the spatial representation and learning process in large scale spaces from those in conventional scale spaces. Here, we developed a 3-meter diameter Barnes maze (BM3), then explored whether spatial learning in the Barnes maze (BM) is calibrated by scale spaces. Spatial learning in the BM3 was successfully established with a lower learning rate than that in a conventional 1-meter diameter Barnes maze (BM1). Specifically, analysis of exploration strategies revealed that the mice in the BM3 persistently searched certain places throughout the learning, while such places were rapidly decreased in the BM1. These results suggest dedicated exploration strategies requiring more trial-and-errors and computational resources in the BM3 than in the BM1, leading to a divergence of s...

Although casual drinkers are a majority of the alcohol drinking population, understanding of the long-term effects of chronic exposure to lower levels of alcohol is limited. Chronic exposure to lower doses of ethanol may facilitate the development of alcohol use disorders, potentially due to ethanol effects on reward learning and motivation. Indeed, our previously published findings showed that chronic low-dose ethanol exposure enhanced motivation for sucrose in male, but not female, mice. As the ventral hippocampus (vHPC) is sensitive to disruption by higher doses of chronic ethanol and tracks reward-related information, we hypothesized that this region is impacted by low-dose ethanol and, further, that manipulating vHPC activity would alter reward motivation. In vivo electrophysiological recordings of vHPC population neural activity during progressive ratio testing revealed that vHPC activity was suppressed in the period immediately after reward seeking (lever press) in ethanol-naïve controls, whereas su...

A central question in the field of aging research is to identify the cellular and molecular basis of neuroresilience. One potential candidate is the small GTPase, Rab10. Here we used Rab10+/- mice to investigate the molecular mechanisms underlying Rab10-mediated neuroresilience. Brain expression analysis of 880 genes involved in neurodegeneration showed that Rab10+/- mice have increased activation of pathways associated with neuronal metabolism, structural integrity, neurotransmission, and neuroplasticity compared to their Rab10+/+ littermates. Lower activation was observed for pathways involved in neuroinflammation and aging. We identified and validated several differentially expressed genes (DEGs) including Stx2, Stx1b, Vegfa, Lrrc25 (downregulated); and Prkaa2, Syt4 and Grin2d (upregulated). Behavioral testing showed that Rab10+/- mice perform better in a hippocampal-dependent spatial task (object in place test), while their performance in a classical conditioning task (trace eyeblink conditioning, TECC...

Lateralization of hippocampal function is indicated by varied outcomes of patients with neurological disorders that selectively affect one hemisphere of this structure, such as temporal lobe epilepsy (TLE). The intrahippocampal kainic acid (IHKA) injection model of TLE allows for targeted damage to the left or right hippocampus, enabling systematic comparison of effects of left-right asymmetry on seizure and non-seizure outcomes. Although varying non-seizure phenotypic outcomes based on injection side in dorsal hippocampus were recently evaluated in this model, differences in chronic seizure patterns in left- (IHKA-L) vs. right-injected (IHKA-R) IHKA animals have yet to be evaluated. Here, we assessed hippocampal seizure incidence in male and female IHKA-L and IHKA-R mice. Females displayed increased electrographic seizure activity compared to males at both 2 and 4 months post-injection. In addition, IHKA-L females showed higher seizure frequency than IHKA-R on diestrus and estrus at 2 months post-injectio...