Chemogenetic techniques such as Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) enable transient, reversible, and minimally invasive manipulation of neural activity in vivo. Their development in non-human primates is essential for uncovering neural circuits contributing to cognitive functions and their translation to humans. One key issue that has delayed the development of chemogenetic techniques in primates is the lack of an accessible drug-screening method. Here, we utilize resting-state functional MRI (rs-fMRI), a non-invasive neuroimaging tool, to assess the impact of deschloroclozapine (DCZ) on brain-wide resting-state functional connectivity in seven rhesus macaques (6 males and 1 female) without DREADDs. We found that systemic administration of 0.1 mg/kg DCZ did not alter the resting-state functional connectivity. Conversely, 0.3 mg/kg of DCZ was associated with a prominent increase in functional connectivity that was mainly confined to the connections of frontal regions. Addit...

For many decades, synaptic plasticity was believed to be restricted to excitatory transmission. However, in recent years, this view started to change, and now it is recognized that GABAergic synapses show distinct forms of activity-dependent long-term plasticity, but the underlying mechanisms remain obscure. Herein we asked whether signaling mediated by β1 or β3 subunit-containing integrins might be involved in regulating the efficacy of GABAergic synapses, including the NMDA receptor-dependent inhibitory long-term potentiation (iLTP) in the hippocampus. We found that activation of β3 integrin with fibrinogen induced a stable depression, whereas inhibition of β1 integrin potentiated GABAergic synapses at CA1 pyramidal neurons in male mice. Additionally, compounds that interfere with the interaction of β1 or β3 integrins with extracellular matrix blocked the induction of NMDA-iLTP. In conclusion, we provide the first evidence that integrins are key players in regulating the endogenous modulatory mechanisms ...

Sensory perception and memory are enhanced during restricted phases of ongoing brain rhythms, but whether voluntary movement is constrained by brain rhythm phase is not known. Voluntary movement requires motor commands to be released from motor cortex (M1) and transmitted to spinal motoneurons and effector muscles. Here, we tested the hypothesis that motor commands are preferentially released from M1 during circumscribed phases of ongoing sensorimotor rhythms. Healthy humans of both sexes performed a self-paced finger movement task during electroencephalography (EEG) and electromyography (EMG) recordings. We first estimated the time of motor command release preceding each finger movement by subtracting individually-measured corticomuscular transmission latencies from EMG-determined movement onset times. Then, we determined the phase of ipsilateral and contralateral sensorimotor mu (8-12 Hz) and beta (13-35 Hz) rhythms during release of each motor command. We report that motor commands were most often relea...

The medial forebrain bundle (MFB) is a white matter pathway that traverses through mesolimbic structures and includes dopaminergic neural fibers ascending from the ventral tegmental area. Since dopaminergic signals represent hedonic responses, electrical stimulation of the MFB in animals has been used as a neural reward for operant and spatial tasks. MFB stimulation strongly motivates animals to rapidly learn to perform a variety of behavioral tasks to obtain a reward. Although the MFB is known to connect various brain regions and MFB stimulation dynamically modulates animal behavior, how central and peripheral functions are affected by MFB stimulation per se is poorly understood. To address this question, we simultaneously recorded electrocorticograms (ECoGs) in the primary motor cortex (M1), primary somatosensory cortex, and olfactory bulb of behaving rats while electrically stimulating the MFB. We found that MFB stimulation increased the locomotor activity of rats. Spectral analysis confirmed that immed...

Chronic musculoskeletal pain (CMP) is a significant burden for Persian Gulf War Veterans (GWV), yet the causes are poorly understood. Brain structure abnormalities are observed in GWV, however relationships with modifiable lifestyle factors such as physical activity (PA) are unknown. We evaluated gray matter volumes and associations with symptoms, PA, and sedentary time in GWV with and without CMP. Ninety-eight GWV (10 females) with CMP and 56 GWV (7 females) controls completed T1 weighted magnetic resonance imaging, pain and fatigue symptom questionnaires, and PA measurement via actigraphy. Regional gray matter volumes were analyzed using voxel-based morphometry and were compared across groups using analysis of covariance. Separate multiple linear regression models were used to test associations between PA intensities, sedentary time, symptoms, and gray matter volumes. Family-wise cluster error rates were used to control for multiple comparisons (α=0.05). GWV with CMP reported greater pain and fatigue sym...

In patch foraging tasks, animals must decide whether to remain with a depleting resource or to leave it in search of a potentially better source of reward. In such tasks, animals consistently follow the general predictions of optimal foraging theory (the Marginal Value Theorem; MVT): to leave a patch when the reward rate in the current patch depletes to the average reward rate across patches. Prior studies implicate an important role for the anterior cingulate cortex (ACC) in foraging decisions based on MVT: within single trials, ACC activity increases immediately preceding foraging decisions, and across trials, these dynamics are modulated as the value of staying in the patch depletes to the average reward rate. Here, we test whether these activity patterns reflect dynamic encoding of decision-variables and whether these signals are directly involved in decision-making. We developed a leaky accumulator model based on the MVT that generates estimates of decision variables within and across trials, and test...

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...