After corticospinal tract damage, reticulospinal connections to motoneurons strengthen preferentially to flexor muscles. This could contribute to the disproportionately poor recovery of extensors often seen after spinal cord injury (SCI) and stroke. In this study, we paired electrical stimulation over the triceps muscle with auditory clicks, using a wearable device to deliver stimuli over a prolonged period of time. Healthy human volunteers wore the stimulation device for ∼6 hours and a variety of electrophysiological assessments were used to measure changes in triceps motor output. In contrast to previous results in the biceps muscle, paired stimulation: 1) did not increase the StartReact effect; 2) did not decrease the suppression of responses to transcranial magnetic brain stimulation (TMS) following a loud sound; 3) did not enhance muscle responses elicited by a TMS coil oriented to induce anterior-posterior current. In a second study, chronic cervical SCI survivors wore the stimulation device for ∼4...

The brain interprets sensory inputs to guide behavior, but behavior itself disrupts sensory inputs. Perceiving a coherent world while acting in it constitutes active perception. For example, saccadic eye movements displace visual images on the retina and yet the brain perceives visual stability. Because this percept of visual stability has been shown to be influenced by prior expectations, we tested the hypothesis that it is Bayesian. The key prediction was that priors would be used more as sensory uncertainty increases. Humans and rhesus macaques reported whether an image moved during saccades. We manipulated both prior expectations and levels of sensory uncertainty. All psychophysical data were compared with the predictions of Bayesian ideal observer models. We found that humans were Bayesian for continuous judgments. For categorical judgments, however, they were anti-Bayesian: they used their priors less with greater uncertainty. We studied this categorical result further in macaques. The animals’ judgm...

Human studies employing intracerebral and transcranial perturbations suggest that the input-output properties of cortical circuits are dramatically affected during sleep in healthy subjects as well as in awake patients with multifocal and focal brain injury. In all these conditions, cortical circuits react to direct stimulation with an initial activation followed by suppression of activity (Off-period) that disrupts the build-up of sustained causal interactions typically observed in healthy wakefulness. The transition to this stereotypical response has important clinical implications, being associated with loss of consciousness or loss of function. Here, we provide a mechanistic explanation of these findings by means of simulations of a cortical-like module endowed with activity-dependent adaptation and mean-field theory. First, we show that fundamental aspects of the local responses elicited in humans by direct cortical stimulation can be replicated by systematically varying the relationships between adap...

About one third of individuals living with epilepsy have treatment-resistant seizures. Alternative therapeutic strategies are thus urgently needed. One potential novel treatment target is microRNA-induced silencing, which is differentially regulated in epilepsy. Inhibitors (antagomirs) of specific microRNAs have shown therapeutic promise in preclinical epilepsy studies; however, these studies were mainly conducted in male rodent models, and research into microRNA regulation in females and by female hormones in epilepsy is scarce. This is problematic because female sex and the menstrual cycle can affect the disease course of epilepsy and may, therefore, also alter the efficacy of potential microRNA-targeted treatments. Here, we used the proconvulsant microRNA miR-324-5p and its target, the potassium channel Kv4.2, as an example to test how microRNA-induced silencing and the efficacy of antagomirs in epilepsy are altered in female mice. We showed that Kv4.2 protein is reduced after seizures in female mice si...

Responding rapidly to visual stimuli is fundamental for many animals. For example, predatory birds and insects alike have amazing target detection abilities, with incredibly short neural and behavioral delays, enabling efficient prey capture. Similarly, looming objects need to be rapidly avoided to ensure immediate survival, as these could represent approaching predators. Male Eristalis tenax hoverflies are non-predatory, highly territorial insects, that perform high-speed pursuits of conspecifics and other territorial intruders. During the initial stages of the pursuit the retinal projection of the target is very small, but this grows to a larger object before physical interaction. Supporting such behaviors, E. tenax and other insects have both target-tuned and loom-sensitive neurons in the optic lobes and the descending pathways. We here show that these visual stimuli are not necessarily encoded in parallel. Indeed, we describe a class of descending neurons that respond to small targets, to looming and t...

The ventral pallidum (VP) is an integral locus in the reward circuitry and a major target of GABAergic innervation of both D1-medium spiny neurons (MSNs) and D2-MSNs from the nucleus accumbens (NAc). The VP contains populations of GABAergic (VPGABA, GAD2(+) or vGlut(-)) and glutamatergic (VPglutamate, GAD2(-) or vGlut(+)) cells that facilitate positive reinforcement and behavioral avoidance, respectively. MSN efferents to the VP exert opponent control over behavioral reinforcement with activation of D1-MSN afferents promoting and D2-MSN afferents inhibiting reward seeking. How this afferent-specific and cell type-specific control of reward-seeking is integrated remains largely unknown. Besides GABA, D1-MSNs co-release substance P to stimulate NK1 receptors and D2-MSNs co-release enkephalin to activate mu-opioid and delta-opioid receptors. These neuropeptides act in the VP to alter appetitive behavior and reward-seeking. Using a combination of optogenetics and patch-clamp electrophysiology in mice we foun...

In 2021, 131 million adult Americans reported drinking alcohol in the last month, despite the well-known consequences of alcohol consumption. While alcohol use disorders are associated with both mood and chronic pain disorders, the relationship between alcohol drinking and affective and nociceptive behaviors remains unclear. Corticotropin releasing factor receptor-1 (CRF1) has been implicated in alcohol drinking, affective states, and pain sensitivity; often in a sex-dependent manner. In order to probe the effects of alcohol drinking on activity of CRF1+ cells and to also test the hypothesis that alcohol drinking is associated with both basal and subsequent affective and nociceptive readouts, we put male and female CRF1:cre:tdTomato rats through a battery of behavioral tests before and after intermittent access to alcohol. Following baseline testing, rats began alcohol (or water) drinking. Females consumed more alcohol in the first week, but there was no effect of sex on overall alcohol intake. Following 3...

Previous diagnostic systems precluded the co-existence of autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) in one person; but, after many clinical reports, such diagnostic criteria were updated to allow their co-occurrence. Despite such a clinical change, the neurobiological bases underpinning the comorbidity remain poorly understood, and whether the ASD+ADHD condition is a simple overlap of the two disorders is unknown. Here, to answer this question, we compared the brain dynamics of high-functioning ASD+ADHD children with age-/sex-/IQ-matched pure ASD, pure ADHD, and typically developing children. Regarding autistic traits, the socio-communicational symptom of the ASD+ADHD children was explained by the same over-stable brain dynamics as seen in pure ASD. In contrast, their ADHD-like traits were grounded on a unique neural mechanism that was unseen in pure ADHD: the core symptoms of pure ADHD were associated with the overly flexible whole-brain dynamics that were triggere...

Long-term synaptic plasticity is mediated via cytosolic calcium concentrations ([Ca2+]). Using a synaptic model which implements calcium-based long-term plasticity via two sources of Ca2+, NMDA receptors and voltage-gated calcium channels (VGCCs), we show in dendritic cable simulations that the interplay between these two calcium sources can result in a diverse array of heterosynaptic effects. When spatially clustered synaptic input produces a local NMDA spike, the resulting dendritic depolarization can activate VGCCs at non-activated spines, resulting in heterosynaptic plasticity. NMDA spike activation at a given dendritic location will tend to depolarize dendritic regions that are located distally to the input site more than dendritic sites that are proximal to it. This asymmetry can produce a hierarchical effect in branching dendrites, where an NMDA spike at a proximal branch can induce heterosynaptic plasticity primarily at branches that are distal to it. We also explored how simultaneously activated s...

The brain interprets sensory inputs to guide behavior, but behavior itself disrupts sensory inputs. Perceiving a coherent world while acting in it constitutes active perception. For example, saccadic eye movements displace visual images on the retina and yet the brain perceives visual stability. Because this percept of visual stability has been shown to be influenced by prior expectations, we tested the hypothesis that it is Bayesian. The key prediction was that priors would be used more as sensory uncertainty increases. Humans and rhesus macaques reported whether an image moved during saccades. We manipulated both prior expectations and levels of sensory uncertainty. All psychophysical data were compared with the predictions of Bayesian ideal observer models. We found that humans were Bayesian for continuous judgments. For categorical judgments, however, they were anti-Bayesian: they used their priors less with greater uncertainty. We studied this categorical result further in macaques. The animals’ judgm...