Following traumatic brain injury (TBI), cognitive impairments manifest through interactions between microscopic and macroscopic changes. On the micro-scale a neurometabolic cascade alters neurotransmission, while on the macro-scale diffuse axonal injury impacts the integrity of long-range connections. Large-scale brain network modeling allows us to make predictions across these spatial scales by integrating neuroimaging data with biophysically based models to investigate how microscale changes invisible to conventional neuroimaging influence large-scale brain dynamics. To this end, we analyzed structural and functional neuroimaging data from a well characterized sample of forty-four adult TBI patients recruited from a regional trauma center, scanned at 1-2 weeks post-injury, and with follow-up behavioral outcome assessed six months later. Thirty-six age-matched healthy adults served as comparison participants. Using The Virtual Brain we fit simulations of whole-brain resting-state functional MRI to the emp...

Spontaneous α oscillations (∼10 Hz) have been associated with various cognitive functions, including perception. Their phase and amplitude independently predict cortical excitability and subsequent perceptual performance. However, the causal role of α phase-amplitude tradeoffs on visual perception remains ill-defined. We aimed to fill this gap and tested two clear predictions from the pulsed inhibition theory according to which α oscillations are associated with periodic functional inhibition. (1) High-α amplitude induces cortical inhibition at specific phases, associated with low perceptual performance, while at opposite phases, inhibition decreases (potentially increasing excitation) and perceptual performance increases. (2) Low-α amplitude is less susceptible to these phasic (periodic) pulses of inhibition, leading to overall higher perceptual performance. Here, cortical excitability was assessed in humans using phosphene (illusory) perception induced by single pulses of transcranial magnetic stimulatio...

Operant chambers are widely used in animal research to study cognition, motivation, and learning processes. Paired with the rapidly developing technologies for brain imaging and manipulations of brain activity, operant conditioning chambers are a powerful tool for neuroscience research. The behavioral testing and imaging setups that are commercially available are often quite costly. Here, we present a custom-built operant chamber that can be constructed in a few days by an unexperienced user with relatively inexpensive, widely available materials. The advantages of our operant setup compared with other open-source and closed-source solutions are its relatively low cost, its support of complex behavioral tasks, its user-friendly setup, and its validated functionality with video imaging of behavior and calcium imaging using the UCLA Miniscope. Using this setup, we replicate our previously published findings showing that mice exposed to social defeat stress in adolescence have inhibitory control impairments i...

Parvalbumin (Pvalb+)- and somatostatin (Sst+)-positive cells are the two largest subgroups of inhibitory interneurons. Studies in visual cortex indicate that synaptic connections between Pvalb+ cells are common while connections between Sst+ interneurons have not been observed. The inhibitory connectivity and kinetics of these two interneuron subpopulations, however, have not been characterized in medial entorhinal cortex (mEC). Using fluorescence-guided paired recordings in mouse brain slices from interneurons and excitatory cells in layer 2/3 mEC, we found that, unlike neocortical measures, Sst+ cells inhibit each other, albeit with a lower probability than Pvalb+ cells (18% versus 36% for unidirectional connections). Gap junction connections were also more frequent between Pvalb+ cells than between Sst+ cells. Pvalb+ cells inhibited each other with larger conductances, smaller decay time constants and shorter delays. Similarly, synaptic connections between Pvalb+ and excitatory cells were more likely an...

Myelin is essential to neuronal health and CNS function, and oligodendrocytes (OLs) undergo a complex process of cytoskeletal remodeling to form compact myelin sheaths. We previously discovered that a formin protein, Daam2, suppresses OL differentiation through Wnt signaling; however, its role in cytoskeletal control remains unknown. To investigate this, we used OL-specific Daam2 deletion (Daam2 cKO) in mice of either sex and found myelin decompaction during an active period of myelination in postnatal development and motor coordination deficits in adulthood. Using primary OL cultures, we found Daam2-depleted OLs showed morphological dysregulation during differentiation, suggesting that Daam2 regulates the OL cytoskeleton. In vivo screening identified the actin regulators Rac1 and Gelsolin as possible effectors in Daam2-deficient OL cytoskeletal regulation. Using gain- and loss-of-function experiments in primary OLs, we found that Rac1 and Gelsolin operate downstream of Daam2 in OL differentiation, with Ge...

Phosphatase and tensin homolog (PTEN) is a major negative regulator of the PI3K/Akt/mechanistic target of rapamycin (mTOR) pathway. Loss-of-function mutations in PTEN have been found in a subset of patients with macrocephaly and autism spectrum disorder. PTEN loss in neurons leads to somal hypertrophy, aberrant migration, dendritic overgrowth, increased spine density, and hyperactivity of neuronal circuits. These neuronal overgrowth phenotypes are present upon Pten knockout (KO) and reconstitution with autism-associated point mutations. The mechanism underlying dendritic overgrowth in Pten deficient neurons is unclear. In this study, we examined how Pten loss impacts microtubule dynamics in both sexes using retroviral infection and transfection strategies to manipulate PTEN expression and tag the plus-end microtubule binding protein, EB3. We found Pten KO neurons sprout more new processes over time compared to wild-type (WT) neurons. We also found an increase in microtubule polymerization rate in Pten KO d...

It is well established that glutamate plays an important role in drug- and cue-induced reinstatement of drug seeking. However, the role of glutamate in drug reward is unclear. In this study, we systemically evaluated the effects of multiple glutamate transporter (GLT) inhibitors on extracellular glutamate and dopamine (DA) in the nucleus accumbens (NAc), intravenous cocaine self-administration, intracranial brain-stimulation reward, and reinstatement of cocaine seeking in male and female rats. Among the 5 GLT inhibitors we tested, TFB-TBOA was the most potent. Microinjections of TFB-TBOA into the NAc, but not the ventral tegmental area (VTA), or dorsal striatum (DS), dose-dependently inhibited cocaine self-administration under fixed-ratio and progressive-ratio reinforcement schedules, shifted the cocaine dose-response curve downward, and inhibited intracranial brain-stimulation reward. Selective downregulation of astrocytic GLT-1 expression in the NAc by GLT-1 antisense oligonucleotides also inhibited coca...

Temporal expectation is the ability to construct predictions regarding the timing of events, based on previously-experienced temporal regularities of different types. For example, cue-based expectations are constructed when a cue validly indicates when a target is expected to occur. However, in the absence of such cues, expectations can be constructed based on contextual temporal information, including the event’s onset distribution and recent prior experiences, both providing implicit probabilistic information regarding the event’s timing. It was previously suggested that cue-based temporal expectation is exerted via synchronization of spatially-specific neural activity at a target's predictable time, within receptive fields corresponding to the target’s expected location. Here, we tested if the same theoretical model holds for contextual temporal effects. Participants (n = 40; 25 females) performed a speeded spatial-cueing detection task, with two-thirds valid spatial cues. The target’s hazard-rate func...

The high sensitivity of night vision requires that rod photoreceptors reliably and reproducibly signal the absorption of single photons, a process that depends upon tight regulation of intracellular cGMP concentration through the phototransduction cascade. Here in the mouse ( Mus musculus ), we studied a single-site D167A mutation of the gene for the alpha subunit of rod photoreceptor phosphodiesterase ( PDEA ), made with the aim of removing a noncatalytic binding site for cGMP. This mutation unexpectedly eliminated nearly all PDEA expression and reduced expression of the beta subunit gene ( PDEB ) to about 5 – 10% of wild-type (WT). The remaining phosphodiesterase had nearly normal specific activity; degeneration was slow, with 50–60% of rods remaining after 6 months. Responses were larger and more sensitive than normal but slower in rise and decay, probably from slower dark turnover of cGMP. Remarkably, responses became much less reproducible than WT, with response variance increasing for amplitude by ov...

Endogenous adenosine plays a crucial role in maintaining energy homeostasis and adenosine levels are tightly regulated across neural circuits. In the dorsal medial striatum (DMS) adenosine inhibits neurotransmitter release, but the source and mechanism underlying its accumulation are largely unknown. Opioids also inhibit neurotransmitter release in the DMS and influence adenosine accumulation after prolonged exposure. However, how these two neurotransmitter systems interact acutely is also largely unknown. This study demonstrates that activation of μ opioid receptors (MORs), but not δ opioid receptors (DORs) or κ opioid receptors (KORs), inhibits tonic activation of adenosine A1Rs via a cyclic adenosine monophosphate (cAMP) dependent mechanism in both male and female mice. Further, selectively knocking-out MORs from thalamic presynaptic terminals and postsynaptic medium spiny neurons (MSNs) revealed that activation of MORs on D1R positive MSNs, but not D2R positive MSNs, is necessary to inhibit tonic adeno...