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 (FRs) 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 before stimulus ...

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...

Nicotine robustly sustains smoking behavior by acting as a primary reinforcer and by enhancing the incentive salience of the nicotine-associated stimuli. The motivational effects produced by environmental cues associated with nicotine delivery can progressively manifest during abstinence resulting in reinstatement of nicotine seeking. However, how the activity in reward neuronal circuits is transformed during abstinence-induced nicotine seeking is not yet fully understood. In here we used a contingent nicotine and saline control self-administration model to disentangle the contribution of cue-elicited seeking responding for nicotine after drug abstinence in male Wistar rats. Using ex vivo electrophysiological recordings and a network analysis approach, we defined temporal and brain-region specific amygdalo-striatal glutamatergic alterations that occur during nicotine abstinence. The results from this study provide critical evidence indicating a persistent hypoglutamatergic state within the amygdalo-striata...

Memory consolidation processes have traditionally been investigated from the perspective of hours or days. However, recent developments in memory research have shown that memory consolidation processes could occur even within seconds, possibly because of the neural replay of just practiced memory traces during short breaks. Here, we investigate this rapid form of consolidation during statistical learning. We aim to answer (1) whether this rapid consolidation occurs in implicit statistical learning and general skill learning, and (2) whether the duration of rest periods affects these two learning types differently. Human participants performed a widely used statistical learning task—the alternating serial reaction time (ASRT) task—that enables us to measure implicit statistical and general skill learning separately. The ASRT task consisted of 25 learning blocks with a rest period between the blocks. In a between-subjects design, the length of the rest periods was fixed at 15 or 30 s, or the participants cou...

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 ...

Facial expressions are an increasingly used tool to assess emotional experience and affective state during experimental procedures in animal models. Previous studies have successfully related specific facial features with different positive and negative valence situations, most notably in relation to pain. However, characterizing and interpreting such expressions remains a major challenge. We identified seven easily visualizable facial parameters on mouse profiles, accounting for changes in eye, ear, mouth, snout and face orientation. We monitored their relative position on the face across time and throughout sequences of positive and aversive gustatory and somatosensory stimuli in freely moving mice. Facial parameters successfully captured response profiles to each stimulus and reflected spontaneous movements in response to stimulus valence, as well as contextual elements such as habituation. Notably, eye opening was increased by palatable tastants and innocuous touch, while this parameter was reduced by ...

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...

Cognitive-behavioral testing in preclinical models of Alzheimer’s disease has failed to capture deficits in goal-directed action control. Here, we provide the first comprehensive investigation of goal-directed action in a transgenic mouse model of Alzheimer’s disease. Specifically, we tested outcome devaluation performance in male and female human amyloid precursor protein (hAPP)-J20 mice. Mice were first trained to press left and right levers for pellet and sucrose outcomes, respectively (counterbalanced), over 4 d. On test, mice were prefed one of the outcomes to satiety and given a choice between levers. Devaluation performance was intact for 36-week-old wild-types of both sexes, who responded more on the valued relative to the devalued lever (Valued > Devalued). By contrast, devaluation was impaired (Valued = Devalued) for J20 mice of both sexes, and for 52-week-old male mice regardless of genotype. After additional lever press training (i.e., 8-d lever pressing in total), devaluation was intact for al...

Microglia invade the neuroblast migratory corridor of the rostral migratory stream (RMS) early in development. The early postnatal RMS does not yet have the dense astrocyte and vascular scaffold that helps propel forward migrating neuroblasts, which led us to consider whether microglia help regulate conditions permissive to neuroblast migration in the RMS. GFP-labeled microglia in CX3CR-1GFP/+ mice assemble primarily along the outer borders of the RMS during the first postnatal week, where they exhibit predominantly an ameboid morphology and associate with migrating neuroblasts. Microglia ablation for 3 d postnatally does not impact the density of pulse labeled BrdU+ neuroblasts nor the distance migrated by tdTomato electroporated neuroblasts in the RMS. However, microglia wrap DsRed-labeled neuroblasts in the RMS of P7 CX3CR-1GFP/+;DCXDsRed/+ mice and express the markers CD68, CLEC7A, MERTK, and IGF-1, suggesting active regulation in the developing RMS. Microglia depletion for 14 d postnatally further ind...

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...