To date, post-traumatic epilepsy (PTE) research in large animal models has been limited. Recent advances in neocortical microscopy have made possible new insights into neocortical PTE. However, it is very difficult to engender convincing neocortical PTE in rodents. Thus, large animal models that develop neocortical PTE may provide useful insights that also can be more comparable to human patients. Because gyrencephalic species have prolonged latent periods, long-term video EEG recording is required. Here, we report a fully subcutaneous EEG implant with synchronized video in freely ambulatory swine for up to 13 months during epileptogenesis following bilateral cortical impact injuries or sham surgery The advantages of this system include the availability of a commercially available system that is simple to install, a low failure rate after surgery for EEG implantation, radiotelemetry that enables continuous monitoring of freely ambulating animals, excellent synchronization to video to EEG, and a robust sign...

Women report greater cigarette cravings during the menstrual cycle phase with higher circulating levels of 17β-estradiol (E2), which is metabolized to estrone (E1). Both E2 and E1 bind to estrogen receptors (ERs), which have been highly studied in the breast, uterus, and ovary. Recent studies have found that ERs are also located on GABAergic medium spiny neurons (MSNs) within the nucleus accumbens core (NAcore). Glutamatergic plasticity in NAcore MSNs is altered following nicotine use; however, it is unknown whether estrogens impact this neurobiological consequence. To test the effect of estrogen on nicotine use, we ovariectomized (OVX) female rats that then underwent nicotine self-administration acquisition and compared them to ovary-intact (sham) rats. The OVX animals then received either sesame oil (vehicle), E2, or E1+E2 supplementation for 4 or 20 days prior to nicotine sessions. While both ovary-intact and OVX females readily discriminated levers, OVX females consumed less nicotine than sham females....

Neurobiological evidence in rodents indicates that threat extinction incorporates reward neurocircuitry. Consequently, incorporating reward associations with an extinction memory may be an effective strategy to persistently attenuate threat responses. Moreover, while there is considerable research on the short-term effects of extinction strategies in humans, the long-term effects of extinction are rarely considered. In a within-subjects fMRI study with both female and male participants, we compared counterconditioning (a form of rewarded-extinction) to standard extinction at recent (24 hours) and remote (∼1 month) retrieval tests. Relative to standard extinction, rewarded extinction diminished 24-hour relapse of arousal and threat expectancy, and reduced activity in brain regions associated with the appraisal and expression of threat (e.g., thalamus, insula, periaqueductal gray). The retrieval of reward-associated extinction memory was accompanied by functional connectivity between the amygdala and the ven...

Language production involves a complex set of computations, from conceptualisation to articulation, which are thought to engage cascading neural events in the language network. However, recent neuromagnetic evidence suggests simultaneous meaning-to-speech mapping in picture naming tasks, as indexed by early parallel activation of fronto-temporal regions to lexical semantic, phonological and articulatory information. Here we investigate the time course of word production, asking to what extent such “earliness” is a distinctive property of the associated spatiotemporal dynamics. Using magnetoencephalography (MEG), we recorded the neural signals of 34 human subjects (26 males) overtly naming 134 images from 4 semantic object categories (animals, foods, tools, clothes). Within each category, we co-varied word length, as quantified by the number of syllables contained in a word, and phonological neighbourhood density to target lexical and post-lexical phonological/phonetic processes. Multivariate pattern analys...

The need to sleep is sensed and discharged in a poorly understood process that is homeostatically controlled over time. In flies, different contributions to this process have been attributed to peripheral ppk and central brain neurons, with the former serving as hypothetical inputs to the sleep homeostat and the latter reportedly serving as the homeostat itself. Here we re-evaluate these distinctions in light of new findings using female flies. First, activating neurons targeted by published ppk and brain drivers elicits similar phenotypes – namely sleep deprivation followed by rebound sleep. Second, inhibiting activity or synaptic output with one type of driver suppresses sleep homeostasis induced using the other type of driver. Third, drivers previously used to implicate central neurons in sleep homeostasis unexpectedly also label ppk neurons. Fourth, activating only this subset of co-labeled neurons is sufficient to elicit sleep homeostasis. Thus, many published contributions of central neurons to sleep...

Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common genetic cause of Parkinson's disease (PD), but the pathogenic mechanism underlying LRRK2 mutations remains unresolved. In this study, we investigate the consequence of inactivation of LRRK2 and its functional homolog LRRK1 in male and female mice up to 25 months of age using behavioral, neurochemical, neuropathological, and ultrastructural analyses. We report that LRRK1 and LRRK2 double knock-out ( LRRK DKO) mice exhibit impaired motor coordination at 12 months of age before the onset of dopaminergic neuron loss in the substantia nigra (SNpc). Moreover, LRRK DKO mice develop age-dependent, progressive loss of dopaminergic terminals in the striatum. Evoked dopamine (DA) release measured by fast-scan cyclic voltammetry in the dorsal striatum is also reduced in the absence of LRRK. Furthermore, LRRK DKO mice at 20–25 months of age show substantial loss of dopaminergic neurons in the SNpc. The surviving SNpc neurons in LRRK DKO mice at 25 mo...

Studies have recently demonstrated that a caspase-2-mediated cleavage of human tau (htau) at asparate-314 (D314) is responsible for cognitive deficits and neurodegeneration in mice modeling frontotemporal dementia (FTD). However, these animal studies may be confounded by flaws in their model systems, such as endogenous functional gene disruption and inequivalent transgene expression. To avoid these weaknesses, we examined the pathogenic role of this site-specific htau cleavage in FTD using genetically matched htau targeted-insertion mouse lines: rT2 and rT3. Both male and female mice were included in this study. rT2 mice contain a single copy of the FTD-linked htau proline-to-leucine mutation at amino acid 301 (htau P301L), inserted into a neutral site to avoid dysregulation of host gene expression. The similarly constructed rT3 mice harbor an additional D314-to-glutamate (D314E) mutation that blocks htau cleavage. We demonstrate that htau transgene expression occurs primarily in the forebrain at similar l...

Recent research revealed a surprisingly large range of cognitive operations to be preserved during sleep in humans. The new challenge is therefore to understand functions and mechanisms of processes, which so far have been mainly investigated in awake subjects. The current study focuses on dynamic changes of brain oscillations and connectivity patterns in response to environmental stimulation during non-REM sleep. Our results indicate that aurally presented names were processed and neuronally differentiated across the wake-sleep spectrum. Simultaneously recorded EEG and MEG signals revealed two distinct clusters of oscillatory power increase in response to the stimuli: (1) vigilance state-independent θ synchronization occurring immediately after stimulus onset, followed by (2) sleep-specific α/σ synchronization peaking after stimulus offset. We discuss the possible role of θ, α, and σ oscillations during non-REM sleep, and work toward a unified theory of brain rhythms and their functions during sleep. SIG...

Stimulus-specific adaptation (SSA) is the reduction in responses to frequent stimuli (standards) that does not generalize to rare stimuli (deviants). We investigated the contribution of inhibition in auditory cortex to SSA using two-photon targeted cell-attached recordings and optogenetic manipulations in male mice. We characterized the responses of parvalbumin (PV)-, somatostatin (SST)-, and vasoactive intestinal polypeptide (VIP)-expressing interneurons of layer 2/3, and of serotonin receptor 5HT3a-expressing interneurons of layer 1. All populations showed early-onset SSA. Unexpectedly, the PV, SST, and VIP populations exhibited a substantial late component of evoked activity, often stronger for standard than for deviant stimuli. Optogenetic suppression of PV neurons facilitated pyramidal neuron responses substantially more (approximately ×10) for deviants than for standards. VIP suppression decreased responses of putative PV neurons, specifically for standard but not for deviant stimuli. Thus, the inhib...

Physical exercise improves motor performance in individuals with Parkinson's disease and elevates mood in those with depression. Although underlying factors have not been identified, clues arise from previous studies showing a link between cognitive benefits of exercise and increases in brain-derived neurotrophic factor (BDNF). Here, we investigated the influence of voluntary wheel-running exercise on BDNF levels in the striatum of young male wild-type (WT) mice, and on the striatal release of a key motor-system transmitter, dopamine (DA). Mice were allowed unlimited access to a freely rotating wheel (runners) or a locked wheel (controls) for 30 d. Electrically evoked DA release was quantified in ex vivo corticostriatal slices from these animals using fast-scan cyclic voltammetry. We found that exercise increased BDNF levels in dorsal striatum (dStr) and increased DA release in dStr and in nucleus accumbens core and shell. Increased DA release was independent of striatal acetylcholine (ACh), and persisted ...