As we navigate the world, we use learned representations of relational structures to explore and to reach goals. Studies of how relational knowledge enables inference and planning are typically conducted in controlled small-scale settings. It remains unclear, however, how people use stored knowledge in continuously unfolding navigation (e.g., walking long distances in a city). We hypothesized that multiscale predictive representations guide naturalistic navigation in humans, and these scales are organized along posterior-anterior prefrontal and hippocampal hierarchies. We conducted model-based representational similarity analyses of neuroimaging data collected while male and female participants navigated realistically long paths in virtual reality. We tested the pattern similarity of each point, along each path, to a weighted sum of its successor points within predictive horizons of different scales. We found that anterior PFC showed the largest predictive horizons, posterior hippocampus the smallest, with...

Ronald McGregor, Ming-Fung Wu, Brent Holmes, Hoa Anh Lam, Nigel T. Maidment, et al. (see pages [255–263][1]) Repeated use of heroin, cocaine, or related drugs can produce long-lasting changes in multiple brain areas, thus promoting continued drug use despite negative consequences. One area

Brain–machine interfaces (BMIs) for reaching have enjoyed continued performance improvements, yet there remains significant need for BMIs that control other movement classes. Recent scientific findings suggest that the intrinsic covariance structure of neural activity depends strongly on movement class, potentially necessitating different decode algorithms across classes. To address this possibility, we developed a self-motion BMI based on cortical activity as monkeys cycled a hand-held pedal to progress along a virtual track. Unlike during reaching, we found no high-variance dimensions that directly correlated with to-be-decoded variables. This was due to no neurons having consistent correlations between their responses and kinematic variables. Yet we could decode a single variable—self-motion—by nonlinearly leveraging structure that spanned multiple high-variance neural dimensions. Resulting online BMI-control success rates approached those during manual control. These findings make two broad points rega...

Temporal coherence of sound fluctuations across spectral channels is thought to aid auditory grouping and scene segregation. Although prior studies on the neural bases of temporal-coherence processing focused mostly on cortical contributions, neurophysiological evidence suggests that temporal-coherence-based scene analysis may start as early as the cochlear nucleus (i.e., the first auditory region supporting cross-channel processing over a wide frequency range). Accordingly, we hypothesized that aspects of temporal-coherence processing that could be realized in early auditory areas may shape speech understanding in noise. We then explored whether physiologically plausible computational models could account for results from a behavioral experiment that measured consonant categorization in different masking conditions. We tested whether within-channel masking of target-speech modulations predicted consonant confusions across the different conditions and whether predictions were improved by adding across-chan...

We previously found that human heroin addicts and mice chronically exposed to morphine exhibit a significant increase in the number of detected hypocretin/orexin (Hcrt)-producing neurons. However, it remains unknown how this increase affects target areas of the hypocretin system involved in opioid withdrawal, including norepinephrine containing structures locus coeruleus (LC) and A1/A2 medullary regions. Using a combination of immunohistochemical, biochemical, imaging, and behavioral techniques, we now show that the increase in detected hypocretin cell number translates into a significant increase in hypocretin innervation and tyrosine hydroxylase (TH) levels in the LC without affecting norepinephrine-containing neuronal cell number. We show that the increase in TH is completely dependent on Hcrt innervation. The A1/A2 regions were unaffected by morphine treatment. Manipulation of the Hcrt system may affect opioid addiction and withdrawal. SIGNIFICANCE STATEMENT Previously, we have shown that the hypothal...

Globally, more than 67 million people are living with the effects of ischemic stroke. Importantly, many stroke survivors develop a chronic inflammatory response that may contribute to cognitive impairment, a common and debilitating sequela of stroke that is insufficiently studied and currently untreatable. 2-Hydroxypropyl-β-cyclodextrin (HPβCD) is an FDA-approved cyclic oligosaccharide that can solubilize and entrap lipophilic substances. The goal of the present study was to determine whether the repeated administration of HPβCD curtails the chronic inflammatory response to stroke by reducing lipid accumulation within stroke infarcts in a distal middle cerebral artery occlusion mouse model of stroke. To achieve this goal, we subcutaneously injected young adult and aged male mice with vehicle or HPβCD 3 times per week, with treatment beginning 1 week after stroke. We evaluated mice at 7 weeks following stroke using immunostaining, RNA sequencing, lipidomic, and behavioral analyses. Chronic stroke infarct an...

Response inhibition is an essential aspect of cognitive control that is necessary for terminating inappropriate preplanned or ongoing responses. Response-selective stopping represents a complex form of response inhibition where only a subcomponent of a multicomponent action must be terminated. In this context, a substantial response delay emerges on unstopped effectors after the cued effector is successfully stopped. This response delay has been termed the stopping interference effect. Converging lines of evidence indicate that this effect results from a global response inhibition mechanism that is recruited regardless of the stopping context. However, behavioral observations reveal that the stopping interference effect may not always occur during selective stopping. This review summarizes the behavioral and neural signatures of response inhibition during selective stopping. An overview of selective stopping contexts and the stopping interference effect is provided. A “restart” model of selective stopping ...

In humans, age-related declines in vision, hearing, and touch coincide with changes in amplitude and latency of sensory-evoked potentials. These age-related differences in neural activity may be related to a common deterioration of supra-modal brain areas (e.g., PFC) that mediate activity in sensory cortices or reflect specific sensorineural impairments that may differ between sensory modalities. To distinguish between these two possibilities, we measured neuroelectric brain activity while 37 young adults (18-30 years, 18 males) and 35 older adults (60-88 years, 20 males) were presented with a rapid randomized sequence of lateralized auditory, visual, and somatosensory stimuli. Within each sensory domain, we compared amplitudes and latencies of sensory-evoked responses, source activity, and functional connectivity (via phase-locking value) between groups. We found that older adults' early sensory-evoked responses were greater in amplitude than those of young adults in all three modalities, which coincided ...

Amacrine cells, inhibitory interneurons of the retina, feature synaptic inputs and outputs in close proximity throughout their dendritic trees, making them notable exceptions to prototypical somato-dendritic integration with output transmitted via axonal action potentials. The extent of dendritic compartmentalization in amacrine cells with widely differing dendritic tree morphology, however, is largely unexplored. Combining compartmental modeling, dendritic Ca2+ imaging, targeted microiontophoresis and multi-electrode patch-clamp recording (voltage and current clamp, capacitance measurement of exocytosis), we investigated integration in the AII amacrine cell, a narrow-field electrically coupled interneuron that participates in multiple, distinct microcircuits. Physiological experiments were performed with in vitro slices prepared from retinas of both male and female rats. We found that the morphology of the AII enables simultaneous local and global integration of inputs targeted to different dendritic regi...

GABAB receptors in habenula cholinergic neurons mediate strong presynaptic excitation and control aversive memory expression. K+ channel tetramerization domain (KCTD) proteins are key interacting partners of GABAB receptors; it remains unclear whether and how KCTDs contribute to GABAB excitatory signaling. Here, we show that KCTD8 and KCTD12 in these neurons facilitate the GABAB receptors expression in axonal terminals and contribute to presynaptic excitation by GABAB receptors. Genetically knocking out KCTD8/12/16 , or KCTD8/12 , but not other combinations of the three KCTD isoforms, substantially reduced GABAB receptors–mediated potentiation of glutamate release and presynaptic Ca2+ entry in response to axonal stimulation, whereas they had no effect on GABAB-mediated inhibition in the somata of cholinergic neurons within the habenulo-interpeduncular pathway in mice of either sex. The physiological phenotypes were associated with a significant decrease in the GABAB expression within the axonal terminals b...