γ-Aminobutyric acid (GABA) is the principal inhibitory neurotransmitter in the adult brain which mediates its rapid effects on neuronal excitability via ionotropic GABAA receptors. GABA levels in the brain are critically dependent upon GABA-aminotransferase (GABA-AT) which promotes its degradation. Vigabatrin, a low-affinity GABA-AT inhibitor, exhibits anticonvulsant efficacy, but its use is limited due to cumulative ocular toxicity. OV329 is a rationally designed, next-generation GABA-AT inhibitor with enhanced potency. We demonstrate that sustained exposure to OV329 in mice reduces GABA-AT activity and subsequently elevates GABA levels in the brain. Parallel increases in the efficacy of GABAergic inhibition were evident, together with elevations in electroencephalographic delta power. Consistent with this, OV329 exposure reduced the severity of status epilepticus and the development of benzodiazepine refractory seizures. Thus, OV329 may be of utility in treating seizure disorders and associated pathologi...

The gaze-following patch (GFP) is located in the posterior temporal cortex and has been described as a cortical module dedicated to processing other people's gaze-direction in a domain-specific manner. Thus, it appears to be the neural correlate of Baron-Cohen's eye direction detector (EDD) which is one of the core modules in his mindreading system—a neurocognitive model for the theory of mind concept. Inspired by Jerry Fodor's ideas on the modularity of the mind, Baron-Cohen proposed that, among other things, the individual modules are domain specific. In the case of the EDD, this means that it exclusively processes eye-like stimuli to extract gaze-direction and that other stimuli, which may carry directional information as well, are processed elsewhere. If the GFP is indeed EDD's neural correlate, it must meet this expectation. To test this, we compared the GFP's BOLD activity during gaze-direction following with the activity during arrow-direction following in the present human fMRI study. Contrary to t...

We investigated the neural signatures of expert decision-making in the context of police training in a virtual reality–based shoot/don’t shoot scenario. Police officers can use stopping force against a perpetrator, which may require using a firearm and each decision made by an officer to discharge their firearm or not has substantial implications. Therefore, it is important to understand the cognitive and underlying neurophysiological processes that lead to such a decision. We used virtual reality–based simulations to elicit ecologically valid behavior from authorized firearms officers (AFOs) in the UK and matched novices in a shoot/don't shoot task and recorded electroencephalography concurrently. We found that AFOs had consistently faster response times than novices, suggesting our task was sensitive to their expertise. To investigate differences in decision-making processes under varying levels of threat and expertise, we analyzed electrophysiological signals originating from the anterior cingulate cort...

The adult turtle spinal cord can generate multiple kinds of limb movements, including swimming, three forms of scratching, and limb withdrawal (flexion reflex), even without brain input and sensory feedback. There are many multifunctional spinal neurons, activated during multiple motor patterns, and some behaviorally specialized neurons, activated during only one. How do multifunctional and behaviorally specialized neurons each contribute to motor output? We analyzed in vivo intracellular recordings of multifunctional and specialized neurons. Neurons tended to spike in the same phase of the hip-flexor (HF) activity cycle during swimming and scratching, though one preferred opposite phases. During both swimming and scratching, a larger fraction of multifunctional neurons than specialized neurons were highly rhythmic. One group of multifunctional neurons was active during the HF-on phase and another during the HF-off phase. Thus, HF–extensor alternation may be generated by a subset of multifunctional spinal ...

Psychotic symptoms and delusional beliefs have been linked to dopamine transmission in both healthy and clinical samples and are assumed to result at least in part from perceiving illusory patterns in noise. However, the existing literature on the role of dopamine in detecting patterns in noise is inconclusive. To address this issue, we assessed the effect of manipulating dopaminergic neurotransmission on illusory pattern perception in healthy individuals ( n  = 48, n  = 19 female) in a double-blind placebo-controlled within-subjects design (see preregistration at <https://osf.io/a4k9j/>). We predicted individuals on versus off ʟ-DOPA to be more likely to perceive illusory patterns, specifically objects in images containing only noise. Using a signal detection model, however, we found no credible evidence that ʟ-DOPA compared with placebo increased false alarm rates. Further, ʟ-DOPA did not reliably modulate measures of accuracy, discrimination sensitivity, and response bias. In all cases, Bayesian statist...

Impaired inhibition—and the resulting disruption of the brain's excitatory–inhibitory (E–I) balance—has historically been theorized to play a critical role in epileptogenesis and seizures (Treiman, 2001). This concept is supported by numerous studies showing impaired function of gamma-aminobutyric acid (GABA)-ergic function in both genetic and acquired animal models of epilepsy and in human epileptic brain tissue. Furthermore, medications that enhance GABAergic signaling have an anticonvulsant effect whereas GABA antagonists are proconvulsant. Yet, despite a large body of evidence implicating GABA in epileptogenesis and epilepsy, the direct causal role of inhibitory interneuron loss (or impairment) has remained incompletely understood. In the case of acquired models of epilepsy, such as temporal lobe epilepsy, interneuron loss is central to signature pathophysiology but occurs alongside multiple other pathological and neuroplastic changes that are also likely to influence disease progression. In the case ...

Acetylcholine (ACh) neurons in the central nervous system are required for the coordination of neural network activity during higher brain functions, such as attention, learning, and memory, as well as locomotion. Disturbed cholinergic signaling has been described in many neurodevelopmental and neurodegenerative disorders. Furthermore, co-transmission of other signaling molecules, such as glutamate and GABA, with ACh has been associated with essential roles in brain function or disease. However, it is unknown when ACh neurons become cholinergic during development. Thus, understanding the timeline of how the cholinergic system develops and becomes active in the healthy brain is a crucial part of understanding brain development. To study this, we used transgenic mice to selectively label ACh neurons with tdTomato. We imaged serial sectioned brains and generated whole-brain reconstructions at different time points during pre- and postnatal development. We found three crucial time windows – two in the prenatal...

γ-aminobutyric acid (GABA) is the principal inhibitory neurotransmitter in the adult brain which mediates its rapid effects on neuronal excitability via ionotropic GABAA receptors. GABA levels in the brain are critically dependent upon GABA-aminotransferase (GABA-AT) which promotes its degradation. Vigabatrin, a low affinity GABA-AT inhibitor, exhibits anticonvulsant efficacy but its use is limited due to cumulative ocular toxicity. OV329 is a rationally designed, next–generation GABA-AT inhibitor with enhanced potency. We demonstrate that sustained exposure to OV329 in mice reduces GABA-AT activity and subsequently elevates GABA levels in the brain. Parallel increases in the efficacy of GABAergic inhibition were evident, together with elevations in EEG delta power. Consistent with this, OV329 exposure reduced the severity of status epilepticus and the development of benzodiazepine refractory seizures. Thus, OV329 may be of utility in treating seizure disorders and associated pathologies that result from n...

Elevated intraocular pressure (IOP) triggers glaucoma by damaging the output neurons of the retina called retinal ganglion cells (RGCs). This leads to the loss of RGC signaling to visual centers of the brain such as the dorsolateral geniculate nucleus (dLGN), which is critical for processing and relaying information to the cortex for conscious vision. In response to altered levels of activity or synaptic input, neurons can homeostatically modulate postsynaptic neurotransmitter receptor numbers, allowing them to scale their synaptic responses to stabilize spike output. While prior work has indicated unaltered glutamate receptor properties in the glaucomatous dLGN, it is unknown whether glaucoma impacts dLGN inhibition. Here, using DBA/2J mice, which develop elevated IOP beginning at 6-7 months of age, we tested whether the strength of inhibitory synapses on dLGN thalamocortical relay neurons is altered in response to the disease state. We found an enhancement of feed-forward disynaptic inhibition arising fr...

Ghrelin is a stomach-derived hormone that increases feeding and is elevated in response to chronic psychosocial stressors. The effects of ghrelin on feeding are mediated by the binding of ghrelin to the growth hormone secretagogue receptor (GHSR), a receptor located in hypothalamic and extra-hypothalamic regions important for regulating food intake and metabolic rate. The ability of ghrelin to enter the brain, however, seems to be restricted to circumventricular organs like the median eminence and the brain stem area postrema (AP), whereas ghrelin does not readily enter other GHSR expressing regions like the ventral tegmental area (VTA). Interestingly, social stressors result in increased blood brain barrier permeability, and this could therefore facilitate the entry of ghrelin into the brain. To investigate this, we exposed mice to social defeat stress for 21 days, then peripherally injected a Cy5-labelled biologically active ghrelin analogue. Results demonstrate that chronically stressed mice exhibit hig...