Temporal lobe epilepsy (TLE) is notoriously pharmacoresistant, and identifying novel therapeutic targets for controlling seizures is crucial. Long-range inhibitory neuronal nitric oxide synthase-expressing cells (LINCs), a population of hippocampal neurons, were recently identified as a unique source of widespread inhibition in CA1, able to elicit both GABAA-mediated and GABAB-mediated postsynaptic inhibition. We therefore hypothesized that LINCs could be an effective target for seizure control. LINCs were optogenetically activated for on-demand seizure intervention in the intrahippocampal kainate (KA) mouse model of chronic TLE. Unexpectedly, LINC activation at 1 month post-KA did not substantially reduce seizure duration in either male or female mice. We tested two different sets of stimulation parameters, both previously found to be effective with on-demand optogenetic approaches, but neither was successful. Quantification of LINCs following intervention revealed a substantial reduction of LINC numbers ...

Oxaliplatin is a platinum-based chemotherapeutic agent that causes cold and mechanical allodynia in up to 90% of patients. Silent Nav1.8-positive nociceptive cold sensors have been shown to be unmasked by oxaliplatin, and this event has been causally linked to the development of cold allodynia. We examined the effects of pregabalin on oxaliplatin-evoked unmasking of cold sensitive neurons using mice expressing GCaMP-3 in all sensory neurons. Intravenous injection of pregabalin significantly ameliorates cold allodynia, while decreasing the number of cold sensitive neurons by altering their excitability and temperature thresholds. The silenced neurons are predominantly medium/large mechano-cold sensitive neurons, corresponding to the “silent” cold sensors activated during neuropathy. Deletion of α2δ1 subunits abolished the effects of pregabalin on both cold allodynia and the silencing of sensory neurons. Thus, these results define a novel, peripheral inhibitory effect of pregabalin on the excitability of “si...

Here, we describe the development, structure, and effectiveness of an outreach program, DrosoPHILA, that leverages the tools of our fly neurodevelopmental research program at the University of Pennsylvania to reinforce the biology curriculum in local public schools. DrosoPHILA was developed and is sustained by a continued collaboration between members of the Bashaw lab, experienced outreach educators, and teachers in the School District of Philadelphia. Since the program’s inception, we have collaborated with 18 teachers and over 2400 students. Student outcome data indicates significant positive attitude shifts around science identity and grade-appropriate knowledge gains.

The motor cortex controls skilled arm movement by recruiting a variety of targets in the nervous system, and it is important to understand the emergent activity in these regions as refinement of a motor skill occurs. One fundamental projection of the motor cortex (M1) is to the cerebellum. However, the emergent activity in the motor cortex and the cerebellum that appears as a dexterous motor skill is consolidated is incompletely understood. Here, we report on low-frequency oscillatory (LFO) activity that emerges in cortico-cerebellar networks with learning the reach-to-grasp motor skill. We chronically recorded the motor and the cerebellar cortices in rats, which revealed the emergence of coordinated movement-related activity in the local-field potentials as the reaching skill consolidated. Interestingly, we found this emergent activity only in the rats that gained expertise in the task. We found that the local and cross-area spiking activity was coordinated with LFOs in proficient rats. Finally, we also f...

Adolescence is a crucial developmental period in terms of behavior and mental health. Therefore, understanding how the brain develops during this stage is a fundamental challenge for neuroscience. Recent studies have modeled the brain as a network or connectome, mainly applying measures from graph theory, showing a change in its functional organization, such as an increase in its segregation and integration. Topological Data Analysis (TDA) complements such modeling by extracting high-dimensional features across the whole range of connectivity values instead of exploring a fixed set of connections. This study inquires into the developmental trajectories of such properties using a longitudinal sample of typically developing human participants ( N  = 98; 53/45 female/male; 6.7–18.1 years), applying TDA to their functional connectomes. In addition, we explore the effect of puberty on individual developmental trajectories. Results showed that the adolescent brain has a more distributed topology structure compar...

Circadian photoperiod, or day length, changes with the seasons and influences behavior to allow animals to adapt to their environment. Photoperiod is also associated with seasonal rhythms of affective state, as evidenced by seasonality of several neuropsychiatric disorders. Interestingly, seasonality tends to be more prevalent in women for affective disorders such as major depressive disorder and bipolar disorder (BD). However, the underlying neurobiological processes contributing to sex-linked seasonality of affective behaviors are largely unknown. Mesolimbic dopamine input to the nucleus accumbens (NAc) contributes to the regulation of affective state and behaviors. Additionally, sex differences in the mesolimbic dopamine pathway are well established. Therefore, we hypothesize that photoperiod may drive differential modulation of NAc dopamine in males and females. Here, we used fast-scan cyclic voltammetry (FSCV) to explore whether photoperiod can modulate subsecond dopamine signaling dynamics in the NAc...

Crisis? What crisis? Is the lack of reproducibility a supertramp that disperses widely across science fields? Is it carelessness, or is it also intrinsic to life sciences as I shall argue? Lack of reproducibility is a big flag brandished by many, but what do they mean by it? Where does it originate from? These were the first questions that crossed my mind as, while in Liège, Belgium for a PhD defense, I was asked to give a talk on the reproducibility crisis. Rather than a formal presentation, we had an open discussion. This editorial is its outcome. According to Wikipedia’s definition of reproducibility, “results obtained by an experiment or an observational study or in a statistical analysis of a data set should be achieved again with a high degree of reliability when the study is replicated” (https://en.wikipedia.org/wiki/Reproducibility). The definition is thus very strict: the results must be replicable, which means that the same experimental conditions or data analysis method must be used. Finding s...

Age-related cognitive decline is related to cellular and systems-level disruptions across multiple brain regions. Because age-related cellular changes within different structures do not show the same patterns of dysfunction, interventions aimed at optimizing function of large-scale brain networks may show greater efficacy at improving cognitive outcomes in older adults than traditional pharmacotherapies. The current study aimed to leverage a preclinical rat model of aging to determine whether cognitive training in young and aged male rats with a computerized paired-associates learning (PAL) task resulted in changes in global resting-state functional connectivity. Moreover, seed-based functional connectivity was used to examine resting state connectivity of cortical areas involved in object-location associative memory and vulnerable in old age, namely the medial temporal lobe (MTL; hippocampal cortex and perirhinal cortex), retrosplenial cortex (RSC), and frontal cortical areas (prelimbic and infralimbic co...

Voluntary movements are prepared before they are executed. Preparatory activity has been observed across the CNS and recently documented in first-order neurons of the human PNS (i.e., in muscle spindles). Changes seen in sensory organs suggest that independent modulation of stretch reflex gains may represent an important component of movement preparation. The aim of the current study was to further investigate the preparatory modulation of short-latency stretch reflex responses (SLRs) and long-latency stretch reflex responses (LLRs) of the dominant upper limb of human subjects. Specifically, we investigated how different target parameters (target distance and direction) affect the preparatory tuning of stretch reflex gains in the context of goal-directed reaching, and whether any such tuning depends on preparation duration and the direction of background loads. We found that target distance produced only small variations in reflex gains. In contrast, both SLR and LLR gains were strongly modulated as a func...

Hyperactivation of the mechanistic target of rapamycin (mTOR) signaling pathway is linked to more than a dozen neurologic diseases, causing a range of pathologies, including excess neuronal growth, disrupted neuronal migration, cortical dysplasia, epilepsy and autism. The mTOR pathway also regulates angiogenesis. For the present study, therefore, we queried whether loss of Pten or Tsc2 , both mTOR negative regulators, alters brain vasculature in three mouse models: one with Pten loss restricted to hippocampal dentate granule cells [DGC- Pten knock-outs (KOs)], a second with widespread Pten loss from excitatory forebrain neurons (FB- Pten KOs) and a third with focal loss of Tsc2 from cortical excitatory neurons (f- Tsc2 KOs). Total hippocampal vessel length and volume per dentate gyrus were dramatically increased in DGC- Pten knock-outs. DGC- Pten knock-outs had larger dentate gyri overall, however, and when normalized to these larger structures, vessel density was preserved. In addition, tests of blood-bra...