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...

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 ...

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 ...

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...

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...

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 (<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" display="inline"><mml:mrow><mml:msub><mml:mi>N</mml:mi><mml:mrow><mml:mi>A</mml:mi><mml:mi>v</mml:mi><mml:mi>o</mml:mi><mml:mi>i</mml:mi><mml:mi>d</mml:mi></mml:mrow></mml:msub></mml:mrow></mml:math> = 545, <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" display="inline"><mml:mrow><mml:msub><mml:mi>N</mml:mi><mml:mrow><mml:mi>R</mml:mi><mml:mi>e</mml:mi>...

Parkinson’s disease (PD) is a progressive neurodegenerative disease that comprises a range of motor and nonmotor symptoms. Glial cell line-derived neurotrophic factor (GDNF) promotes the survival of dopamine neurons in vitro and in vivo , and intracranial delivery of GDNF has been tested in six clinical trials for treating PD. However, clinical trials with ectopic GDNF have yielded variable results, which could in part result from abnormal expression site and levels caused by ectopic overexpression. Therefore, an important open question is whether an increase in endogenous GDNF expression could be potent in reversing PD progression. Here, we tested the therapeutic potential of endogenous GDNF using mice in which endogenous GDNF can be conditionally upregulated specifically in cells that express GDNF naturally (conditional GDNF hypermorphic mice; GdnfcHyper ). We analyzed the impact of endogenous GDNF upregulation in both neuroprotection and neurorestoration procedures, and for both motor and nonmotor sympt...

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...