The behavioral tagging (BT) hypothesis provides crucial insights into the mechanism of long-term memory (LTM) consolidation. Novelty exposure in BT is a decisive step in activating the molecular machinery of memory formation. Several studies have validated BT using different neurobehavioral tasks; however, the novelty given in all studies is open field (OF) exploration. Environment enrichment (EE) is another key experimental paradigm to explore the fundamentals of brain functioning. Recently, several studies have highlighted the importance of EE in enhancing cognition, LTM, and synaptic plasticity. Hence, in the present study, we investigated the effects of different types of novelty on LTM consolidation and plasticity-related protein (PRP) synthesis using the BT phenomenon. Novel object recognition (NOR) was used as the learning task for rodents (male Wistar rats), while OF and EE were two types of novel experiences provided to the rodents. Our results indicated that EE exposure efficiently leads to LTM c...

To survive in a complex and changing environment, animals must adapt their behavior. This ability is called behavioral flexibility and is classically evaluated by a reversal learning paradigm. During such a paradigm, the animals adapt their behavior according to a change of the reward contingencies. To study these complex cognitive functions (from outcome evaluation to motor adaptation), we developed a versatile, low-cost, open-source platform, allowing us to investigate the neuronal correlates of behavioral flexibility with 1-photon calcium imaging. This platform consists of FreiBox, a novel low-cost Arduino behavioral setup, as well as further open-source tools, which we developed and integrated into our framework. FreiBox is controlled by a custom Python interface and integrates a new licking sensor (strain gauge lickometer) for controlling spatial licking behavioral tasks. In addition to allowing both discriminative and serial reversal learning, the Arduino can track mouse licking behavior in real time...

The apolipoprotein E gene ( APOE ) confers the greatest genetic risk factor for Alzheimer’s disease (AD), wherein the ε4 allele confers an elevated risk compared with the ε3 allele. Biological mechanisms that differ across these alleles have been explored in mouse models wherein the murine Apoe gene has undergone targeted replacement with sequences encoding human ApoE3 or ApoE4 (ApoE-TR mice). Such models have indicated that the two variants of ApoE produce differential effects on energy metabolism, including metabolic syndrome. However, glucose regulation has not been compared in ApoE-TR mice with and without amyloid β-peptide (Aβ) accumulation. We crossed ApoE3-TR and ApoE4-TR mice with a transgenic line that accumulates human Aβ1-42. In male ApoE3-TR mice, introduction of Aβ caused aberrations in glucose tolerance and in membrane translocation of astrocytic glucose transporter 1 (GLUT1). Phosphorylation of Tau at AD-relevant sites was correlated with glucose intolerance. These effects appeared independe...

Brain function depends on complex circuit interactions between excitatory and inhibitory neurons embedded in local and long-range networks. Systemic GABAA-receptor (GABAAR) or NMDA-receptor (NMDAR) modulation alters the excitatory-inhibitory balance (EIB), measurable with electroencephalography (EEG). However, EEG signatures are complex in localization and spectral composition. We developed and applied analytical tools to investigate the effects of two EIB modulators, MK801 (NMDAR antagonist) and diazepam (GABAAR modulator), on periodic and aperiodic EEG features in freely-moving male Sprague Dawley rats. We investigated how, across three brain regions, EEG features are correlated with EIB modulation. We found that the periodic component was composed of seven frequency bands that presented region-dependent and compound-dependent changes. The aperiodic component was also different between compounds and brain regions. Importantly, the parametrization into periodic and aperiodic components unveiled correlatio...

Loss-of-function mutations in neuroligin-4 (Nlgn4), a member of the neuroligin family of postsynaptic adhesion proteins, cause autism spectrum disorder in humans. Nlgn4 knockout (KO) in mice leads to social behavior deficits and complex alterations of synaptic inhibition or excitation, depending on the brain region. In the present work, we comprehensively analyzed synaptic function and plasticity at the cellular and network levels in hippocampal dentate gyrus of Nlgn4 KO mice. Compared with wild-type littermates, adult Nlgn4 KO mice exhibited increased paired-pulse inhibition of dentate granule cell population spikes, but no impairments in excitatory synaptic transmission or short-term and long-term plasticity in vivo . In vitro patch-clamp recordings in neonatal organotypic entorhino-hippocampal slice cultures from Nlgn4 KO and wild-type littermates revealed no significant differences in excitatory or inhibitory synaptic transmission, homeostatic synaptic plasticity, and passive electrotonic properties in...

Taste cells are maintained by continuous turnover throughout a lifetime, yet the mechanisms of taste cell differentiation, and how taste sensations remain constant despite this continuous turnover, remain poorly understood. Here, we report that a transcription factor Etv1 (also known as Er81) is involved in the differentiation of taste cells responsible for the preference for sweet, umami, and salty tastes. Molecular analyses revealed that Etv1 is expressed by a subset of taste cells that depend on Skn-1a (also known as Pou2f3) for their generation and express T1R genes (responsible for sweet and umami tastes) or Scnn1a (responsible for amiloride-sensitive salty taste). Etv1CreERT2/CreERT2 mice express Etv1 isoform(s) but not Etv1 in putative proprioceptive neurons as comparable to wild-type mice, yet lack expression of Etv1 or an isoform in taste cells. These Etv1CreERT2/CreERT2 mice have the same population of Skn-1a-dependent cells in taste buds as wild-type mice but have altered gene expression in tast...

Midbrain dopamine (DA) neurons are among the best characterized pacemaker neurons, having intrinsic, rhythmic firing activity even in the absence of synaptic input. However, the mechanisms of DA neuron pacemaking have not been systematically related to how these cells respond to synaptic input. The input–output properties of pacemaking neurons can be characterized by the phase-resetting curve (PRC), which describes the sensitivity of interspike interval (ISI) length to inputs arriving at different phases of the firing cycle. Here we determined PRCs of putative DA neurons in the substantia nigra pars compacta in brain slices from male and female mice using gramicidin-perforated current-clamp recordings with electrical noise stimuli applied through the patch pipette. On average, and compared with nearby putative GABA neurons, DA neurons showed a low, nearly constant level of sensitivity across most of the ISI, but individual cells had PRCs showing relatively greater sensitivity at early or late phases. Pharm...

The occurrence of tics in Tourette syndrome (TS) has often been linked to impaired cognitive control, but empirical findings are still inconclusive. A recent view proposes that tics may be the result of an abnormally strong interrelation between perceptual processes and motor actions, commonly referred to as perception-action binding. The general aim of the present study was to examine proactive control and binding effects in the context of task switching in adult human patients with TS and matched healthy controls. A cued task switching paradigm was employed in 24 patients (18 male, 6 female) and 25 controls while recording electroencephalography (EEG). Residue iteration decomposition (RIDE) was applied to analyze cue-locked proactive cognitive control and target-locked binding processes. Behavioral task switching performance was unaltered in patients with TS. A cue-locked parietal switch positivity, reflecting proactive control processes involved in the reconfiguration of the new task did not differ betw...

Anxiety is one of the most common psychiatric disorders diagnosed in the United States today. Like all mental illnesses, anxiety pathology includes genetic, molecular, somatic, and behavioral characteristics. Specific brain regions implicated in anxiety include the prefrontal cortex, amygdala, hippocampus, and hypothalamus. Together, these regions regulate fear-related learning and memory processes, and are innervated by neuronal projections that use glutamate and GABA as neurotransmitters. Neurotrophic factors such as brain-derived neurotrophic factor (BDNF) are also implicated in anxiety. This review discusses the neuroepigenetics of the anxiety phenotype. While studying such changes is limited to postmortem brain studies or peripheral tissue acquisition in humans, the use of animals to model anxiety phenotypes has made epigenetic research possible. In this review, we summarize and discuss a plethora of DNA methylation, histone modification, and associated gene expression differences underscoring the anx...

Previous investigation of cognitive processes using transcranial magnetic stimulation (TMS) have explored the response to different stimulation parameters such as frequency and coil location. In this study, we attempt to add another parameter by exploiting the spatial profiles of TMS coils to infer regional information concerning reward-related behavior. We used different TMS coils to modulate activity in the prefrontal cortex (PFC) and examined resulting changes in behavior and associated brain activity. More specifically, we used the Figure-8 coil to stimulate a portion of the dorsolateral PFC (DLPFC) and the H-Coil to stimulate a larger volume within the lateral PFC (LPFC). Healthy human volunteers completed behavioral questionnaires ( n  = 29) or performed a reward-related decision-making functional MRI (fMRI) task ( n  = 21) immediately before and after acute high-frequency stimulation (10 Hz) with either a Figure-8 coil, H-Coil, or a sham coil. Stimulation was found to induce behavioral changes as we...