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...

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 ...

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...

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...

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...

We must often decide how much effort to exert or withhold to avoid undesirable outcomes or obtain rewards. In depression and anxiety, levels of avoidance can be excessive and reward-seeking may be reduced. Yet outstanding questions remain about the links between motivated action/inhibition and anxiety and depression levels, and whether they differ between men and women. Here we examined the relationship between anxiety and depression scores, and performance on effortful active and inhibitory avoidance (Study 1) and reward seeking (Study 2) in humans. Undergraduates and paid online workers ( NAvoid = 545, NReward = 310; NFemale = 368, NMale = 450, MAge = 22.58, RangeAge = 17-62) were assessed on the Beck Depression Inventory II (BDI) and the Beck Anxiety Inventory (BAI) and performed an instructed online avoidance or reward-seeking task. Participants had to make multiple presses on active trials and withhold presses on inhibitory trials to avoid an unpleasant sound (Study 1) or obtain points towards a monet...

Temporal lobe epilepsy (TLE) is notoriously pharmacoresistant, and identifying novel therapeutic targets for controlling seizures is crucial. LINCs, a population of hippocampal neurons, were recently identified as a unique source of widespread inhibition in CA1, able to elicit both GABAA- 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 (IHKA) mouse model of chronic TLE. Unexpectedly, LINC activation at one 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 compared to saline-injected controls. We also observed a decreased number of...

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 2,400 students. Student outcome data indicates significant positive attitude shifts around science identity and grade-appropriate knowledge gains. Significance statement Outreach programming creates connections between scientists and their communities while expanding students’ perception of what science entails and who practices it. As such, outreach programming can act as one part of a multi-pronged approach to diversify the scientific workforce. To build sustainable, effectiv...

Hippocampal neuronal activity at a time preceding stimulus onset affects episodic memory performance. We hypothesized that neuronal activity preceding an event supports successful memory formation; therefore, we explored whether a characterized encoding-associated brain activity, viz. the neuronal activity preceding a stimulus, predicts subsequent memory formation. To address this issue, we assessed the activity of single neurons recorded from the hippocampus in humans, while participants performed word memory tasks. Human hippocampal single-unit activity elicited by a fixation cue preceding words increased the firing rates and predicted whether the words are recalled in a subsequent memory test; this indicated that successful memory formation in humans can be predicted by a preceding stimulus activity during encoding. However, the predictive effect of preceding stimulus activity did not occur during retrieval. These findings suggest that the preparative arrangement of brain activity prior to stimulus enco...