The ventromedial and ventro-anterior-lateral (VM/VAL) motor thalamus is a key junction within the brain circuits sustaining normal and pathological motor control functions and decision making. In this area of thalamus, on one hand, the inhibitory nigro-thalamic pathway provides a main output from the basal ganglia, and on the other hand motor thalamo-cortical loops are involved in the maintenance of ramping preparatory activity before goal directed movements. To better understand the nigral impact on thalamic activity, we recorded electrophysiological responses from VM/VAL neurons while male and female mice were performing a delayed right/left decision licking task. Analysis of correct and error trials revealed that thalamic ramping activity was stronger for premature licks (impulsive action), and weaker for trials with no licks (omission) compared to correct trials. Suppressing ramping activity through optogenetic activation of nigral terminals in the motor thalamus during the delay epoch of the task led...

Proper perception of sounds in the environment requires auditory signals to be encoded with extraordinary temporal precision up to tens of microseconds, but how it originates from the hearing organs in the periphery is poorly understood. In particular, sound-evoked spikes in auditory afferent fibers in vivo are phase-locked to sound frequencies up to 5 kHz, but it is not clear how hair cells can handle intracellular Ca2+ changes with such high speed and efficiency. In this study, we combined patch-clamp recording and two-photon Ca2+ imaging to examine Ca2+ dynamics in hair cell ribbon synapses in the bullfrog amphibian papilla of both sexes. We found that Ca2+ clearance from single synaptic ribbons followed a double exponential function, and the weight of the fast component, but not the two time constants, was significantly reduced for prolonged stimulation, and during inhibition of the plasma membrane Ca2+ ATPase (PMCA), the mitochondrial Ca2+ uptake (MCU), or the sarcolemma/endoplasmic reticulum Ca2+ ATP...

Sleep, a state of quiescence associated with growth and restorative processes, is conserved across species. Invertebrates including the nematode Caenorhabditis elegans exhibit sleep-like states during development, satiety and stress. Here we describe behavior and neural activity during sleep and awake states in adult C. elegans hermaphrodites using new microfluidic methods. We observed effects of fluid flow, oxygen, feeding, odors, and genetic perturbations on long-term sleep behavior over 12 h. We developed a closed-loop sleep detection system to automatically deliver chemical stimuli to assess sleep-dependent changes to evoked neural responses in individual animals. Sleep increased the arousal threshold to aversive stimulation, yet the associated sensory neuron and first-layer interneuron responses were unchanged. This localizes adult sleep-dependent neuromodulation within interneurons presynaptic to the premotor interneurons, rather than afferent sensory circuits. However, sleep prolonged responses in a...

Cognitive deficits following traumatic brain injury (TBI) remain a major cause of disability and early-onset dementia, and there is increasing evidence that chronic neuroinflammation occurring after TBI plays an important role in this process. However, little is known about the molecular mechanisms responsible for triggering and maintaining chronic inflammation after TBI. Here, we identify complement, and specifically complement-mediated microglial phagocytosis of synapses, as a pathophysiological link between acute insult and a chronic neurodegenerative response that is associated with cognitive decline. Three months after an initial insult, there is ongoing complement activation in the injured brain of male C57BL/6 mice, which drives a robust chronic neuroinflammatory response extending to both hemispheres. This chronic neuroinflammatory response promotes synaptic degeneration and predicts progressive cognitive decline. Synaptic degeneration was driven by microglial phagocytosis of complement opsonized s...

A central goal of neuroscience research is to understand how experiences modify brain circuits to guide future adaptive behavior. In response to environmental stimuli, neural circuit activity engages gene regulatory mechanisms within each cell. This activity-dependent gene expression is governed, in part, by epigenetic processes that can produce persistent changes in both neural circuits and the epigenome itself. The complex interplay between circuit activity and neuronal gene regulation is vital to learning and memory, and, when disrupted, is linked to debilitating psychiatric conditions, such as substance use disorder. To develop clinical treatments, it is paramount to advance our understanding of how neural circuits and the epigenome cooperate to produce behavioral adaptation. Here, we discuss how new genetic tools, used to manipulate neural circuits and chromatin, have enabled the discovery of epigenetic processes that bring about long-lasting changes in behavior relevant to mental health and disease.

Existing non-invasive stimulation protocols can generate plasticity in the motor cortex and its corticospinal projections; techniques for inducing plasticity in sub-cortical circuits and alternative descending pathways such as the reticulospinal tract are less well developed. One possible approach developed by this laboratory pairs electrical muscle stimulation with auditory clicks, using a wearable device to deliver stimuli during normal daily activities. In this study, we applied a variety of electrophysiological assessments to male and female healthy human volunteers during a morning and evening laboratory visit. In the intervening time (∼6 hours), subjects wore the stimulation device, receiving three different protocols, in which clicks and stimulation of the biceps muscle were paired at either low or high rate, or delivered at random. Paired stimulation: 1) increased the extent of reaction time shortening by a loud sound (the StartReact effect); 2) decreased the suppression of responses to transcrania...

Cognitive control helps us to overcome task interference in challenging situations. Resolving conflicts due to interfering influences is believed to rely on midfrontal theta oscillations. However, different sources of interference necessitate different types of control. Attentional control is needed to suppress salient distractors. Motor control is needed to suppress goal-incompatible action impulses. While previous studies mostly studied the additive effects of attentional and motor conflicts, we independently manipulated the need for attentional control (via visual distractors) and motor control (via unexpected response deviations) in an EEG study with male and female humans. We sought to find out whether these different types of control rely on the same midfrontal oscillatory mechanisms. Motor conflicts, but not attentional conflicts, elicited increases in midfrontal theta power during conflict resolution. Independent of the type of conflict, theta power was predictive of motor slowing. Connectivity ana...

Computation of expected values, i.e., probability times magnitude, seems to be a dynamic integrative process performed by the brain for efficient economic behavior. However, neural dynamics underlying this computation is largely unknown. Using lottery tasks in monkeys (Macaca mulatta, male; Macaca fuscata, female), we examined 1) whether four core reward-related brain regions detect and integrate probability and magnitude cued by numerical symbols and 2) whether these brain regions have distinct dynamics in the integrative process. Extraction of the mechanistic structure of neural population signals demonstrated that expected value signals simultaneously arose in the central orbitofrontal cortex (cOFC, area 13M) and ventral striatum (VS). Moreover, these signals were incredibly stable compared to weak and/or fluctuating signals in the dorsal striatum and medial OFC. Temporal dynamics of these stable expected value signals were unambiguously distinct: sharp and gradual signal evolutions in the cOFC and VS, ...

Covert spatial attention has a variety of effects on the responses of individual neurons. However, relatively little is known about the net effect of these changes on sensory population codes, even though perception ultimately depends on population activity. Here, we measured the electroencephalogram (EEG) in human observers (male and female), and isolated stimulus-evoked activity that was phase-locked to the onset of attended and ignored visual stimuli. Using an encoding model, we reconstructed spatially selective population tuning functions from the pattern of stimulus-evoked activity across the scalp. Our EEG-based approach allowed us to measure very early visually evoked responses occurring ∼100 ms after stimulus onset. In Experiment 1, we found that covert attention increased the amplitude of spatially tuned population responses at this early stage of sensory processing. In Experiment 2, we parametrically varied stimulus contrast to test how this effect scaled with stimulus contrast. We found that the...

In complex everyday environments, action selection is critical for optimal goal-directed behavior. This refers to the process of choosing a proper action from the range of possible alternatives. The neural mechanisms underlying action selection and how these are affected by normal aging remain to be elucidated. In the present cross-sectional study, we studied processes of effector selection during a multilimb reaction time task in a lifespan sample of healthy human adults ( N = 89; 20-75 years; 48 males, 41 females). Participants were instructed to react as quickly and accurately as possible to visually cued stimuli representing single-limb or combined upper and/or lower limb motions. Diffusion MRI was used to study structural connectivity between prefrontal and striatal regions as critical nodes for action selection. Behavioral findings revealed that increasing age was associated with slowing of action selection performance. At the neural level, aging had a negative impact on prefronto-striatal connectivi...