Inhibitory synaptic mechanisms oppose epileptic network activity in the brain. The breakdown in this inhibitory restraint and propagation of seizure activity has been linked to the overwhelming of feedforward inhibition, which is provided in large part by parvalbumin-expressing (PV) interneurons in the cortex. The underlying cellular processes therefore represent potential targets for understanding and preventing the propagation of seizure activity. Here we use an optogenetic strategy to test the hypothesis that depolarization block in PV interneurons is a significant factor during the loss of inhibitory restraint. Depolarization block results from the inactivation of voltage-gated sodium channels and leads to impaired action potential firing. We used focal NMDA stimulation to elicit reproducible epileptiform discharges in hippocampal organotypic brain slices from male and female mice, and combined this with targeted recordings from defined neuronal populations. Simultaneous patch-clamp recordings from PV ...

Although bottom-up attention can improve visual performance with and without awareness to the exogenous cue, whether they are governed by a common neural computation remains unclear. Using a modified Posner paradigm with backward masking, we found that the cueing effect displayed a monotonic gradient profile (Gaussian-like), both with and without awareness, whose scope, however, was significantly wider with than without awareness. This awareness-dependent scope offered us a unique opportunity to change the relative size of the attention field to the stimulus, differentially modulating the gain of attentional selection, as proposed by the normalization model of attention. Therefore, for each human subject (male and female), the stimulus size was manipulated as their respective mean attention fields with and without awareness while stimulus contrast was varied in a spatial cueing task. By measuring the gain pattern of contrast-response functions (CRFs) on the spatial cueing effect derived by visible or invis...

Neuronal underpinning of learning cause-and-effect associations in the adolescent brain remains poorly understood. Two fundamental forms of associative learning are Pavlovian (classical) conditioning, where a stimulus is followed by an outcome, and operant (instrumental) conditioning, where outcome is contingent on action execution. Both forms of learning, when associated with a rewarding outcome, rely on midbrain dopamine neurons in the VTA and substantia nigra (SN). We find that, in adolescent male rats, reward-guided associative learning is encoded differently by midbrain dopamine neurons in each conditioning paradigm. Whereas simultaneously recorded VTA and SN adult neurons have a similar phasic response to reward delivery during both forms of conditioning, adolescent neurons display a muted reward response during operant but a profoundly larger reward response during Pavlovian conditioning. These results suggest that adolescent neurons assign a different value to reward when it is not gated by action....

Amygdala abnormalities characterize several psychiatric disorders with prominent social deficits and often emerge during adolescence. The basolateral amygdala (BLA) bidirectionally modulates social behavior and has increased sensitivity during adolescence. We tested how an environmentally-driven social state is regulated by the BLA in adults and adolescent male rats. We found that a high social drive state caused by brief social isolation increases age-specific social behaviors and increased BLA neuronal activity. Chemogenetic inactivation of BLA decreased the effect of high social drive on social engagement. High social drive preferentially enhanced BLA activity during social engagement; however, the effect of social opportunity on BLA activity was greater during adolescence. While this identifies a substrate underlying age differences in social drive, we then determined that high social drive increased BLA NMDA GluN2B expression and sensitivity to antagonism increased with age. Further, the effect of a h...

Age-related hearing loss (presbycusis) is a chronic health condition that affects 1/3 of the world’s population. One hallmark of presbycusis is a difficulty hearing in noisy environments. Presbycusis can be separated into two components: alterations of peripheral mechanotransduction of sound in the cochlea, and central alterations of auditory processing areas of the brain. While the effects of the aging cochlea in hearing loss have been well studied, the role of the aging brain in hearing loss is less well understood. Therefore, to examine how age-related central processing changes affect hearing in noisy environments, we used a mouse model (Thy1-GCaMP6s X CBA mice) that has excellent peripheral hearing in old age. We used in vivo 2-photon Ca2+ imaging to measure the responses of neuronal populations in auditory cortex (ACtx) of adult (2-6 months, 9 male, 6 female, 4,180 neurons) and aging (15-17 months, 6 male, 3 female, 1055 neurons) while listening to tones in noisy backgrounds. We found that ACtx neuro...

Team flow occurs when a group functions in a high task engagement to achieve a goal, commonly seen in performance and sports. Team flow can enable enhanced positive experiences, as compared to individual flow or regular socializing. However, the neural basis for this enhanced behavioral state remains unclear. Here, we identified neural correlates of team flow in human participants using a music rhythm task with electroencephalogram hyperscanning. Experimental manipulations held the motor task constant while disrupting the corresponding hedonic music to interfere with the flow state or occluding the partner's positive feedback to impede team interaction. We validated these manipulations by using psychometric ratings and an objective measure for the depth of flow experience, which uses the auditory-evoked potential of a task-irrelevant stimulus. Spectral power analysis at both the scalp sensors and anatomical source levels revealed higher beta-gamma power specific to team flow in the left middle temporal cor...

Human epidemiologic studies implicate exposure to infection during gestation in the etiology of neurodevelopmental disorders. Animal models of maternal immune activation (MIA) have identified the maternal immune response as the critical link between maternal infection and aberrant offspring brain and behavior development. Here we evaluate neurodevelopment of male rhesus monkeys ( Macaca mulatta ) born to MIA-treated dams ( n =14) injected with a modified form of the viral mimic, Polyinosinic:polycytidylic acid (Poly IC) at the end of the first trimester. Control dams received saline injections at the same gestational time points ( n =10) or were untreated ( n =4). MIA-treated dams exhibited a strong immune response as indexed by transient increases in sickness behavior, temperature, and inflammatory cytokines. Although offspring born to control or MIA-treated dams did not differ on measures of physical growth and early developmental milestones, the MIA-treated animals exhibited subtle changes in cognitive ...

Pathological tau modifications are characteristic of Alzheimer’s disease and related dementias, but mechanisms of tau toxicity continue to be debated. Inherited mutations in tau cause early-onset frontotemporal lobar dementias (FTLD-tau) and are commonly used to model mechanisms of tau toxicity in tauopathies. Previous work in the isolated squid axoplasm model demonstrated that several pathogenic forms of tau inhibit axonal transport through a mechanism involving activation of protein phosphatase 1 (PP1). Here, we determined that P301L and R5L FTLD mutant tau proteins elicit a toxic effect on axonal transport as monomeric proteins. We also evaluated interactions between wild type and mutant tau with specific PP1 isoforms (α, β and γ), further examining their contribution to this toxic effect using primary rat hippocampal neurons from both sexes. Pulldown and bioluminescence resonance energy transfer experiments revealed selective interactions of wild type tau with PP1α and PP1γ isoforms, but not PP1β, whic...

Human behavior is biased by past experience. For example, when intercepting a moving target, the speed of previous targets will bias responses in future trials. Neural mechanisms underlying this so-called serial dependence are still under debate. Here, we tested the hypothesis that the previous trial leaves a neural trace in brain regions associated with encoding task-relevant information in visual and/or motor regions. We reasoned that injecting noise by means of transcranial magnetic stimulation (TMS) over premotor and visual areas would degrade such memory traces and hence reduce serial dependence. To test this hypothesis, we applied bursts of TMS pulses to right visual motion processing region hV5/MT+ and to left dorsal premotor cortex during inter-trial intervals of a coincident timing task performed by twenty healthy human participants (15 female). Without TMS, participants presented a bias towards the speed of the previous trial when intercepting moving targets. TMS over dorsal premotor cortex decre...

Frustrative nonreward is a construct in the Negative Valence Systems domain of the Research Domain Criteria (RDoC) from the US National Institute of Mental Health. An organism’s response to frustrating situations (e.g. inability to obtain an expected reward) has broad implications for a variety of neuropsychiatric conditions, including substance use disorders. The current project developed a first of its kind rat operant behavioral model of frustrative nonreward based loosely on the human Point Subtraction Aggression Paradigm. The current study shows that individual differences in frustrative nonreward for sucrose pellets are consistent across sessions at baseline and that the task is sensitive to reward size in male rats. More importantly, high frustrative nonreward behavior for sucrose predicts early “breaking” for intravenous fentanyl self-administration under a progressive ratio schedule. These results solidify frustration/frustrative nonreward as an important factor for substance use disorders in addi...