The classic basal ganglia circuit model asserts a complete segregation of the two striatal output pathways. Empirical data argue that, in addition to indirect-pathway striatal projection neurons (iSPNs), direct-pathway striatal projection neurons (dSPNs) innervate the external globus pallidus (GPe). However, the functions of the latter were not known. In this study, we interrogated the organization principles of striatopallidal projections and their roles in full-body movement in mice (both males and females). In contrast to the canonical motor-promoting response of dSPNs in the dorsomedial striatum (DMSdSPNs), optogenetic stimulation of dSPNs in the dorsolateral striatum (DLSdSPNs) suppressed locomotion. Circuit analyses revealed that dSPNs selectively target Npas1+ neurons in the GPe. In a chronic 6-hydroxydopamine lesion model of Parkinson’s disease, the dSPN-Npas1+ projection was dramatically strengthened. As DLSdSPN-Npas1+ projection suppresses movement, the enhancement of this projection represents a...

Tau deposition begins in the medial temporal lobe (MTL) in aging and Alzheimer’s disease (AD), and MTL neural dysfunction is commonly observed in these groups. However, the association between tau and MTL neural activity has not been fully characterized. We investigated the effects of tau on repetition suppression, the reduction of activity for repeated stimulus presentations compared to novel stimuli. We used task-based functional MRI to assess MTL subregional activity in 21 young (YA) and 45 cognitively normal human older adults (OA; total sample: 37 females, 29 males). AD pathology was measured with position emission tomography (PET), using 18F-Flortaucipir for tau and 11C-Pittsburgh compound B for amyloid-β. The MTL was segmented into six subregions using high-resolution structural images. We compared the effects of low tau pathology, restricted to entorhinal cortex and hippocampus (Tau- OA), to high tau pathology, also occurring in temporal and limbic regions (Tau+ OA). Low levels of tau (Tau- OA vs. ...

The axon initial segment (AIS) is a specialized neuronal compartment in which synaptic input is converted into action potential output. This process is supported by a diverse complement of sodium, potassium, and calcium channels (CaV). Different classes of sodium and potassium channels are scaffolded at specific sites within the AIS, conferring unique functions, but how calcium channels are functionally distributed within the AIS is unclear. Here, we utilize conventional 2-photon laser scanning and diffraction-limited, high-speed spot 2-photon imaging to resolve action potential-evoked calcium dynamics in the AIS with high spatiotemporal resolution. In mouse layer 5 prefrontal pyramidal neurons, calcium influx was mediated by a mix of CaV2 and CaV3 channels that differentially localized to discrete regions. CaV3 functionally localized to produce nanodomain hotspots of calcium influx that coupled to ryanodine-sensitive stores, whereas CaV2 localized to non-hotspot regions. Thus, different pools of CaVs appe...

Cognitive processes that require spatial information rely on synaptic plasticity in the dorsal CA1 area (dCA1) of the hippocampus. Since the function of the hippocampus is impaired in aged individuals, it remains unknown how aged animals make spatial choices. Here, we used IntelliCage to study behavioral processes that support spatial choices of aged female mice living in a group. As a proxy of training-induced synaptic plasticity, we analyzed the morphology of dendritic spines and the expression of a synaptic scaffold protein, PSD-95. We observed that spatial choice training in young adult mice induced correlated shrinkage of dendritic spines and downregulation of PSD-95 in dCA1. Moreover, long-term depletion of PSD-95 by shRNA in dCA1 limited correct choices to a reward corner, while reward preference was intact. In contrast, old mice used behavioral strategies characterized by an increased tendency for perseverative visits and social interactions. This strategy resulted in a robust preference for the re...

Neuromodulatory communication among various neurons and non-neuronal cells mediates myriad physiological and pathologic processes, yet defining regulatory and functional features of neuromodulatory transmission remains challenging because of limitations of available monitoring tools. Recently developed genetically encoded neuromodulatory transmitter sensors, when combined with superresolution and/or deconvolution microscopy, allow the first visualization of neuromodulatory transmission with nanoscale or microscale spatiotemporal resolution. In vitro and in vivo experiments have validated several high-performing sensors to have the qualities necessary for demarcating fundamental synaptic properties of neuromodulatory transmission, and initial analysis has unveiled unexpected fine control and precision of neuromodulation. These new findings underscore the importance of synaptic dynamics in synapse-, subcellular-, and circuit-specific neuromodulation, as well as the prospect of genetically encoded transmitter...

Stress-induced depression is common worldwide. NAc, a “reward” center, is recently reported to be critical to confer the susceptibility to chronic social defeat stress (CSDS) and the depression-related outcome. However, the underlying molecular mechanisms have not been well characterized. In this study, we induced depression-like behaviors with CSDS and chronic mild stress in male mice to mimic social and environmental factors, respectively, and observed animal behaviors with social interaction test, tail suspension test, and sucrose preference test. To determine the role of neuronal nitric oxide synthase (nNOS) and its product nitric oxide (NO), we used brain region-specifically nNOS overexpression and stereotaxic injection of NO inhibitor or donor. Moreover, the downstream molecular cyclin-dependent kinase 5 (CDK5) was explored by conditional KO and gene mutation. We demonstrate that nNOS-implicated mechanisms in NAc shell (NAcSh), including increased cell number, increased protein expression levels, and...

Unexpected and thus surprising events are omnipresent and oftentimes require adaptive behavior such as unexpected inhibition or unexpected action. The current theory of unexpected events suggests that such unexpected events just like global stopping recruit a fronto-basal-ganglia network. A global suppressive effect impacting ongoing motor responses and cognition is specifically attributed to the subthalamic nucleus (STN). Previous studies either used separate tasks or presented unexpected, task-unrelated stimuli during response inhibition tasks to relate the neural signature of unexpected events to that of stopping. Here, we aimed to test these predictions using a within task design with identical stimulus material for both unexpected action and unexpected inhibition using functional magnetic resonance imaging (fMRI) for the first time. To this end, 32 healthy human participants of both sexes performed a cue-informed go/nogo task comprising expected and unexpected action and inhibition trials during fMRI....

Chronic stress impairs the function of multiple brain regions and causes severe hedonic and motivational deficits. One brain region known to be susceptible to these effects is the PFC. Neurons in this region, specifically neuronal projections from the prelimbic region (PL) to the nucleus accumbens core (NAcC), have a significant role in promoting motivated approach. However, little is known about how activity in this pathway changes during associative learning to encode cues that promote approach. Less is known about how activity in this pathway may be altered by stress. In this study, an intersectional fiber photometry approach was used in male Sprague Dawley rats engaged in a Pavlovian autoshaping design to characterize the involvement of the PL-NAcC pathway in the typical acquisition of learned approach (directed at both the predictive cue and the goal), and its potential alteration by stress. Specifically, the hypothesis that neural activity in PL-NAcC would encode a Pavlovian approach cue and that pri...

In humans, the occipital middle-temporal region (hMT+/V5) specializes in the processing of visual motion, while the planum temporale (hPT) specializes in auditory motion processing. It has been hypothesized that these regions might communicate directly to achieve fast and optimal exchange of multisensory motion information. Here we investigated, for the first time in humans (male and female), the presence of direct white matter connections between visual and auditory motion-selective regions using a combined fMRI and diffusion MRI approach. We found evidence supporting the potential existence of direct white matter connections between individually and functionally defined hMT+/V5 and hPT. We show that projections between hMT+/V5 and hPT do not overlap with large white matter bundles, such as the inferior longitudinal fasciculus and the inferior frontal occipital fasciculus. Moreover, we did not find evidence suggesting the presence of projections between the fusiform face area and hPT, supporting the funct...

Gambling disorder (GD) is a behavioral addiction associated with impairments in value-based decision-making and behavioral flexibility and might be linked to changes in the dopamine system. Maximizing long-term rewards requires a flexible trade-off between the exploitation of known options and the exploration of novel options for information gain. This exploration-exploitation trade-off is thought to depend on dopamine neurotransmission. We hypothesized that human gamblers would show a reduction in directed (uncertainty-based) exploration, accompanied by changes in brain activity in a fronto-parietal exploration-related network. Twenty-three frequent, non-treatment seeking gamblers and twenty-three healthy matched controls (all male) performed a four-armed bandit task during functional magnetic resonance imaging (fMRI). Computational modeling using hierarchical Bayesian parameter estimation revealed signatures of directed exploration, random exploration, and perseveration in both groups. Gamblers showed a ...