Recent studies suggest that choice behavior in reinforcement learning tasks is shaped by the level of outcome controllability. In particular, Pavlovian bias (PB) seems to be enhanced under low levels of control, manifesting in approach tendencies toward rewards and response inhibition when facing potential losses. The medial prefrontal cortex (mPFC) has been implicated both in evaluating outcome controllability and in the recruitment of cognitive control (CC) to suppress maladaptive PB during reinforcement learning. The current study tested whether high-definition transcranial direct current stimulation (HD-tDCS) above the mPFC of healthy humans can influence PB, and counteract the previously documented, deleterious behavioral effects of low outcome controllability on decision-making. In a preregistered, between-group, double-blind study ( N  = 103 adults, both sexes), we tested the interaction between controllability and HD-tDCS on parameters of choice behavior in a Go/NoGo task. Relative to sham stimulat...

Molecular, anatomic, and behavioral studies show that the hippocampus is structurally and functionally heterogeneous, with dorsal hippocampus implicated in mnemonic processes and spatial navigation and ventral hippocampus involved in affective processes. By performing electrophysiological recordings of large neuronal populations in dorsal and ventral CA1 in head-fixed mice navigating a virtual environment, we found that this diversity resulted in different strategies for population coding of space. Populations of neurons in dorsal CA1 showed more complex patterns of activity, which resulted in a higher dimensionality of neural representations that translated to more information being encoded, as compared ensembles in vCA1. Furthermore, a pairwise maximum entropy model was better at predicting the structure of these global patterns of activity in ventral CA1 as compared with dorsal CA1. Taken together, the different coding strategies we uncovered likely emerge from anatomic and physiological differences alo...

Recent evidence suggests that alteration of axon initial segment (AIS) geometry (i.e., length or location along the axon) contributes to CNS dysfunction in neurological diseases. For example, AIS length is shorter in the prefrontal cortex of type 2 diabetic mice with cognitive impairment. To determine the key type 2 diabetes-related factor that produces AIS shortening we modified levels of insulin, glucose, or the reactive glucose metabolite methylglyoxal in cultures of dissociated cortices from male and female mice and quantified AIS geometry using immunofluorescent imaging of the AIS proteins AnkyrinG and βIV spectrin. Neither insulin nor glucose modification altered AIS length. Exposure to 100 but not 1 or 10 μm methylglyoxal for 24 h resulted in accumulation of the methylglyoxal-derived advanced glycation end-product hydroimidazolone and produced reversible AIS shortening without cell death. Methylglyoxal-evoked AIS shortening occurred in both excitatory and putative inhibitory neuron populations and i...

The opioid epidemic led to an increase in the number of neonatal opioid withdrawal syndrome (NOWS) cases in infants born to opioid-dependent mothers. Hallmark features of NOWS include weight loss, severe irritability, respiratory problems, and sleep fragmentation. Mouse models provide an opportunity to identify brain mechanisms that contribute to NOWS. Neonatal outbred Swiss Webster Cartworth Farms White (CFW) mice were administered morphine (15 mg/kg, s.c.) twice daily from postnatal day 1 (P1) to P14, an approximation of the third trimester of human gestation. Female and male mice underwent behavioral testing on P7 and P14 to determine the impact of opioid exposure on anxiety and pain sensitivity. Ultrasonic vocalizations (USVs) and daily body weights were also recorded. Brainstems containing pons and medulla were collected during morphine withdrawal on P14 for RNA sequencing. Morphine induced weight loss from P2 to P14, which persisted during adolescence (P21) and adulthood (P50). USVs markedly increase...

Forming long-term memories is crucial for adaptive behavior and survival in changing environments. The molecular consolidation processes which underlie the formation of these long-term memories are dependent on protein synthesis in excitatory and SST-expressing neurons. A centrally important, parallel process to this involves the removal of the memory constraint quinone reductase 2 (QR2), which has been recently shown to enhance memory consolidation for novel experiences in the cortex and hippocampus, via redox modulation. However, it is unknown within which cell type in the cortex removal of QR2 occurs, nor how this affects neuronal function. Here, we use novel taste learning in the mouse anterior insular cortex (aIC) to show that similarly to mRNA translation, QR2 removal occurs in excitatory and SST-expressing neurons. Interestingly, both novel taste and QR2 inhibition reduce excitability specifically within SST, but not excitatory neurons. Furthermore, reducing QR2 expression in SST, but not in PV or e...

In the mature mouse retina, Otx2 is expressed in both retinal pigmented epithelium (RPE) and photoreceptor (PR) cells, and Otx2 knock-out (KO) in the RPE alone results in PR degeneration. To study the cell-autonomous function of OTX2 in PRs, we performed PR-specific Otx2 KO (cKO) in adults. As expected, the protein disappears completely from PR nuclei but is still observed in PR inner and outer segments while its level concomitantly decreases in the RPE, suggesting a transfer of OTX2 from RPE to PRs in response to Otx2 ablation in PRs. The ability of OTX2 to transfer from RPE to PRs was verified by viral expression of tagged-OTX2 in the RPE. Transferred OTX2 distributed across the PR cytoplasm, suggesting functions distinct from nuclear transcription regulation. PR-specific Otx2 cKO did not alter the structure of the retina but impaired the translocation of PR arrestin-1 on illumination changes, making mice photophobic. RNA-seq analyses following Otx2 KO revealed downregulation of genes involved in the cyt...

Savings have been described as the ability of healthy humans to relearn a previously acquired motor skill faster than the first time, which in the context of motor adaptation suggests that the learning rate in the brain could be adjusted when a perturbation is recognized. Alternatively, it has been argued that apparent savings were the consequence of a distinct process that instead of reflecting a change in the learning rate, revealed an explicit re-aiming strategy. Based on recent evidence that feedback adaptation may be central to both planning and control, we hypothesized that this component could genuinely accelerate relearning in human adaptation to force fields (FFs) during reaching. Consistent with our hypothesis, we observed that on re-exposure to a previously learned FF, the very first movement performed by healthy volunteers in the relearning context was better adapted to the external disturbance, and this occurred without any anticipation or cognitive strategy because the relearning session was ...

Convincing evidence of blood-spinal cord barrier (BSCB) alterations has been demonstrated in amyotrophic lateral sclerosis (ALS) and barrier repair is imperative to prevent motor neuron dysfunction. We showed benefits of human bone marrow-derived CD34+ cells (hBM34+) and endothelial progenitor cells (hBM-EPCs) intravenous transplantation into symptomatic G93A SOD1 mutant mice on barrier reparative processes. These gains likely occurred by replacement of damaged endothelial cells, prolonging motor neuron survival. However, additional investigations are needed to confirm the effects of administered cells on integrity of the microvascular endothelium. The aim of this study was to determine tight junction protein levels, capillary pericyte coverage, microvascular basement membrane, and endothelial filamentous actin (F-actin) status in spinal cord capillaries of G93A SOD1 mutant mice treated with human bone marrow-derived stem cells. Tight junction proteins were detected in the spinal cords of cell-treated vers...

Spontaneous recognition memory tasks are widely used to assess cognitive function in rodents and have become commonplace in the characterization of rodent models of neurodegenerative, neuropsychiatric and neurodevelopmental disorders. Leveraging an animal’s innate preference for novelty, these tasks use object exploration to capture the what, where and when components of recognition memory. Choosing and optimizing objects is a key feature when designing recognition memory tasks. Although the range of objects used in these tasks varies extensively across studies, object features can bias exploration, influence task difficulty and alter brain circuit recruitment. Here, we discuss the advantages of using 3D-printed objects in rodent spontaneous recognition memory tasks. We provide strategies for optimizing their design and usage, and offer a repository of tested, open-source designs for use with commonly used rodent species. The easy accessibility, low-cost, renewability and flexibility of 3D-printed open-sou...

Repetition is an indispensable component of motor skill acquisition. However, it is unknown how consistent repeated movement patterns must be to engage an implicit “use-dependent” learning mechanism. In this Registered Report, we tackled this question through a combination of computational modeling, simulations, and behavioral experiments involving visually-guided treadmill walking. Our hypotheses were formalized by two distinct computational models: in the two-process Strategy plus Use-Dependent model, use-dependent learning is viewed as a slowly updating and slowly decaying bias in the direction of repeated movements. The Adaptive Bayesian model frames use-dependent learning as an emergent property of quickly adapting prior probabilities of target step lengths. Critically, the Adaptive Bayesian model is much more sensitive to variable practice than the Strategy plus Use-Dependent model. To test these hypotheses, human participants ( N  = 18, 10 females) learned a novel asymmetric stepping pattern under t...