Humans rapidly update the control of an ongoing movement following changes in contextual parameters. This involves adjusting the controller to exploit redundancy in the movement goal, such as when reaching for a narrow or wide target, and adapting to dynamic changes such as velocity-dependent force fields (FFs). Although flexible control and motor adaptation are computationally distinct, the fact that both unfold within the same movement suggests that they interact functionally to support task-specific adjustments. To test this hypothesis, we conducted a series of experiments combining changes in the target structure and a force field presented separately or in combination. Seventy-six human participants (both sexes) took part in this study, with each experiment involving different participants. They were asked to reach for a target that could change from a narrow square to a wide rectangle between or during trials. Step loads were used to assess whether participants exploited target redundancy. In a separ...

Alzheimer's disease (AD) has traditionally been associated with amyloid-β plaques, but growing evidence underscores the role of neuroinflammation in disease progression. The autoinflammatory hypothesis of AD suggests chronic immune dysfunction contributes to neuronal damage, making immune modulation a promising therapeutic strategy. Cannabidiol (CBD), a phytocannabinoid with anti-inflammatory properties, may offer therapeutic potential. This study investigates how CBD independently influences two key neuroinflammatory regulators in AD: the indoleamine 2,3-dioxygenase (IDO) pathway and the cyclic GMP-AMP synthase (cGAS) pathway. Though mechanistically distinct, both shape CNS immune responses. Targeting these immune-metabolic axes provides a mechanistic alternative to amyloid- or tau-based approaches by addressing upstream drivers of neuroinflammation and immune dysregulation. Using the male 5XFAD transgenic AD mouse model, we administered CBD via inhalation and assessed IDO and cGAS expression using flow c...

This study aims to examine the changes in AQP4 polarity and pericyte vascularity during temporal lobe epilepsy (TLE) progression, with the goal of identifying potential drug targets or strategies to delay the onset and progression of TLE. Chronic TLE was induced in male rats using pilocarpine. AQP4 polarity and pericyte vascular coverage were assessed by immunofluorescence. The effects of modulating AQP4 polarity on PTZ-induced TLE model using male mice were studied. Molecular mechanisms of AQP4 polarity were explored using transwell coculture and transcriptomics, validated at the protein level. ELISA was used to measure PDGF-BB levels in serum and cerebrospinal fluid. Following pilocarpine-induced chronic TLE model establishment, AQP4 polarity and pericyte vascular coverage rapidly increased but later declined, reaching the lowest levels in epileptic animals. Trifluoperazine prevented AQP4 redistribution, reduced seizure duration, and alleviated brain edema in PTZ-induced TLE mouse model. Transcriptomic a...

Aberrant dopamine transmission is a hallmark of several psychiatric disorders. Dopamine neurons in the ventral tegmental area (VTA) display distinct activity states that are regulated by discrete afferent inputs. For example, burst firing requires excitatory input from the mesopontine tegmentum, while dopamine neuron population activity, defined as the number of spontaneously active dopamine neurons, is thought to be dependent on inhibitory drive from the ventral pallidum (VP). Rodent models used to study psychiatric disorders, such as psychosis, consistently exhibit elevated dopamine neuron population activity, due to decreased tonic inhibition from the VP. However, it remains unclear whether the VP can modulate all dopamine neurons or if only a specific subset of VTA dopamine neurons receive innervation from the VP to be recruited as required. This knowledge is critical for understanding dopamine regulation in normal and pathological conditions. Here, we used in vivo electrophysiology in male and female ...

Despite various histological, electrophysiological, and imaging studies, the topographic organization of saccade-related activity in the posterior parietal cortex (PPC) has been notoriously difficult to characterize. In part, this is because areas of interest in PPC are often embedded deep in sulci in macaques and humans. Understanding the extent of topographic organization in PPC can provide insights into the computation contributions of PPC. The lissencephalic cortex of the common marmoset offers a unique opportunity to investigate fine-scale topographic organization in PPC. Recordings were obtained from the PPC of two male marmosets performing a visually guided center-out saccade task with 8 or 36 peripheral targets using multichannel electrode arrays with 100 μm spacing. By plotting the pattern of saccade direction tuning preferences across all penetrations and cortical depths, we uncovered topographic organizational features within the PPC. Like other primates, multiunits in marmoset PPC tend to prefe...

Recent investigations have revealed that selective attention to lateralized speech increases ipsilateral tonic electromyographic activity in the vestigial human auriculomotor system. However, it has yet to be determined whether this modulation depends upon predictive cues that are inherent in continuous speech or whether it is a general concomitant of selective attention to sounds in the auditory periphery. The present study addressed this question by replacing speech with randomized, unpredictable sequences of brief tonal stimuli in a dichotic listening task that necessitated a sustained anticipatory focus of attention. Participants (8 female, 23 male) were presented with sequences of brief tone bursts in one ear and frequency-modulated “chirps” in the other ear and were instructed to focus on sounds in one ear and report attenuated deviant stimuli in that ear. Posterior auricular muscle (PAM) activity was recorded behind both ears, and non-rectified stimulus-locked responses were assessed to ensure the r...

The parabrachial (PB) nucleus participates in taste processing and integration with other senses. PB neurons that express the Calca gene support sensory-integrative responses, albeit only limited data have addressed their influence on taste. Here we investigated how chemogenetic dampening of PB- Calca neurons affected mouse orosensory preferences for diverse taste stimuli in brief-access fluid exposure tests, which capture oral sensory/tongue control of licking behavior. Intracranial delivery of Cre-dependent viruses in female and male Calca Cre/+ mice induced expression of the inhibitory designer receptor hM4Di:mCherry (hM4Di mice) or fluorophore mCherry alone (mCherry control mice) in PB- Calca neurons. Several weeks later, hM4Di and mCherry mice entered brief-access tests where they could lick solutions during discrete, seconds-long trials. Stimuli included concentration series of the behaviorally avoided bitter taste stimuli quinine and cycloheximide, the appetitive sugar sucrose, and mildly cool water...

Social interactions are fundamental to human cognition, with the right temporoparietal junction (rTPJ) playing a key role in integrating motor coordination and social inference. While transcranial random noise stimulation (tRNS) is a promising technique for modulating cortical excitability in real time, its effect on dynamic social processes remains largely unexplored. This study applied high-definition tRNS (HD-tRNS) over the rTPJ during an interactive task to modulate motor coordination and social inference. Eighty neurotypical adults (49 female) were equally distributed across two experiments: Experiment 1, a block design with randomized active and sham stimulation blocks; or Experiment 2, a trial-by-trial design with intermixed stimulation protocols. Participants performed a coordination task with a covert virtual partner programmed to behave cooperatively or competitively. Kinematic data and self-reported attributions of humanness and cooperativeness were analyzed. The results showed that HD-tRNS over...

Careers in translational drug discovery offer exciting opportunities to apply your biomedical research training to the development of much-needed treatments for disease. While pursuing a career in drug discovery in the past has meant exiting the academic setting to join the pharmaceutical industry, this is no longer the case. Translational drug discovery efforts are occurring in a variety of settings including those in academia and the government. This Neuroscience 2017 event provides an overview of career opportunities in the pharmaceutical industry, academic drug discovery centers, and NIH Intramural Research Programs and showcases examples of how basic and innovative biology can be turned into a drug discovery program in a variety of research settings that will lead to new medicines for patients who need them.

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