Conditional deletion of neurexin-2 impaired behavioral flexibility to alterations in action-outcome contingency.

Neurexins (Nrxns) are critical for synapse organization and their mutations have been documented in autism spectrum disorder, schizophrenia, and epilepsy. We recently reported that conditional deletion of Nrxn2, under the control of Emx1Cre promoter, predominately expressed in the neocortex and hippocampus (Emx1-Nrxn2 cKO mice) induced stereotyped patterns of behavior in mice, suggesting behavioral inflexibility. In this study, we investigated the effects of Nrxn2 deletion through two different conditional approaches targeting presynaptic cortical neurons projecting to dorsomedial striatum on the flexibility between goal-directed and habitual actions in response to devaluation of action-outcome (A-O) contingencies in an instrumental learning paradigm or upon reversal of A-O contingencies in a water T-maze paradigm.

Spindle oscillations in communicating axons within a reconstituted hippocampal formation are strongest in CA3 without thalamus.

Spindle-shaped waves of oscillations emerge in EEG scalp recordings during human and rodent non-REM sleep. The association of these 10-16 Hz oscillations with events during prior wakefulness suggests a role in memory consolidation. Human and rodent depth electrodes in the brain record strong spindles throughout the cortex and hippocampus, with possible origins in the thalamus.

Astrocyte-neuron lactate shuttle plays a pivotal role in sensory-based neuroprotection in a rat model of permanent middle cerebral artery occlusion.

We have previously demonstrated protection from impending cortical ischemic stroke is achievable by sensory stimulation of the ischemic area in an adult rat model of permanent middle cerebral artery occlusion (pMCAo). We have further demonstrated that a major underpinning mechanism that is necessary for such protection is the system of collaterals among cerebral arteries that results in reperfusion of the MCA ischemic territory. However, since such collateral flow is weak, it may be necessary but not sufficient for protection and therefore we sought other complementary mechanisms that contribute to sensory-based protection.

The reach of reactivation: Effects of consciously-triggered versus unconsciously-triggered reactivation of associative memory.

Newly formed memories are not passively stored for future retrieval; rather, they are reactivated offline and thereby strengthened and transformed. However, reactivation is not a uniform process: it occurs throughout different states of consciousness, including conscious rehearsal during wakefulness and unconscious processing during both wakefulness and sleep. In this study, we explore the consequences of reactivation during conscious and unconscious awake states.

Regional variation in cholinergic terminal activity determines the non-uniform occurrence of cortical slow waves during REM sleep in mice.

Sleep consists of two basic stages: non-rapid eye movement (NREM) and rapid eye movement (REM) sleep. NREM sleep is characterized by slow high-amplitude cortical electroencephalogram (EEG) signals, while REM sleep is characterized by desynchronized cortical rhythms. Despite this, recent electrophysiological studies have suggested the presence of slow waves (SWs) in local cortical areas during REM sleep.

Memory consolidation during sleep involves context reinstatement in humans.

New memories are not quarantined from each other when first encoded; rather, they are interlinked with memories that were encoded in temporal proximity or that share semantic features. By selectively biasing memory processing during sleep, here we test whether context influences sleep consolidation. Participants first formed 18 idiosyncratic narratives, each linking four objects together.

Reap while you sleep: Consolidation of memories differs by how they were sown.

Newly formed memories are spontaneously reactivated during sleep, leading to their strengthening. This reactivation process can be manipulated by reinstating learning-related stimuli during sleep, a technique termed targeted memory reactivation. Numerous studies have found that delivering cues during sleep improves memory for simple associations, in which one cue reactivates one tested memory.

Context matters: changes in memory over a period of sleep are driven by encoding context.

During sleep, recently acquired episodic memories (i.e., autobiographical memories for specific events) are strengthened and transformed, a process termed consolidation.

Associations between community-level patterns of prenatal alcohol and tobacco exposure on brain structure in a non-clinical sample of 6-year-old children: a South African pilot study.

The current small study utilised prospective data collection of patterns of prenatal alcohol and tobacco exposure (PAE and PTE) to examine associations with structural brain outcomes in 6-year-olds and served as a pilot to determine the value of prospective data describing community-level patterns of PAE and PTE in a non-clinical sample of children. Participants from the Safe Passage Study in pregnancy were approached when their child was ∼6 years old and completed structural brain magnetic resonance imaging to examine with archived PAE and PTE data ( = 51 children-mother dyads). Linear regression was used to conduct whole-brain structural analyses, with false-discovery rate (FDR) correction, to examine: (a) main effects of PAE, PTE and their interaction; and (b) predictive potential of data that reflect of PAE and PTE (e.

GTP energy dependence of endocytosis and autophagy in the aging brain and Alzheimer's disease.

Increased interest in the aging and Alzheimer's disease (AD)-related impairments in autophagy in the brain raise important questions about regulation and treatment. Since many steps in endocytosis and autophagy depend on GTPases, new measures of cellular GTP levels are needed to evaluate energy regulation in aging and AD. The recent development of ratiometric GTP sensors (GEVALS) and findings that GTP levels are not homogenous inside cells raise new issues of regulation of GTPases by the local availability of GTP.

Age-Related Oxidative Redox and Metabolic Changes Precede Intraneuronal Amyloid-β Accumulation and Plaque Deposition in a Transgenic Alzheimer's Disease Mouse Model.

Background: Many identified mechanisms could be upstream of the prominent amyloid-β (Aβ) plaques in Alzheimer's disease (AD).

Objective: To profile the progression of pathology in AD.

Methods: We monitored metabolic signaling, redox stress, intraneuronal amyloid-β (iAβ) accumulation, and extracellular plaque deposition in the brains of 3xTg-AD mice across the lifespan.

Neurons learn by predicting future activity.

Understanding how the brain learns may lead to machines with human-like intellectual capacities. It was previously proposed that the brain may operate on the principle of predictive coding. However, it is still not well understood how a predictive system could be implemented in the brain.

Spatiotemporal structure of sensory-evoked and spontaneous activity revealed by mesoscale imaging in anesthetized and awake mice.

Stimuli-evoked and spontaneous brain activity propagates across the cortex in diverse spatiotemporal patterns. Despite extensive studies, the relationship between spontaneous and evoked activity is poorly understood. We investigate this relationship by comparing the amplitude, speed, direction, and complexity of propagation trajectories of spontaneous and evoked activity elicited with visual, auditory, and tactile stimuli using mesoscale wide-field imaging in mice.

Support for an inhibitory model of word retrieval.

Word retrieval may involve an inhibitory process in which a target word is activated and related words are suppressed. In the current functional magnetic resonance imaging (fMRI) study, we examined the inhibition of language processing cortex by the left dorsolateral prefrontal cortex (DLPFC) during word retrieval using an anagram-solving paradigm. Participants were presented with a distractor that was read aloud followed by a to-be-solved anagram.

Causal Contribution of Awake Post-encoding Processes to Episodic Memory Consolidation.

Stable representations of past experience are thought to depend on processes that unfold after events are initially encoded into memory. Post-encoding reactivation and hippocampal-cortical interactions are leading candidate mechanisms thought to support memory retention and stabilization across hippocampal-cortical networks. Although putative consolidation mechanisms have been observed during sleep and periods of awake rest, the direct causal contribution of awake consolidation mechanisms to later behavior is unclear, especially in humans.

Limitations of the GENSAT Egr1-EGFP transgenic mouse strain for neural circuit activity mapping.

Transgenic immediate-early gene reporter mouse strains are valuable tools for studying activity-dependent neural cell populations in vivo. However, routine characterization of the Gene Expression Nervous System Atlas (GENSAT) "Egr1-EGFP" reporter mouse strain produced results that were highly inconsistent with endogenous Egr1 expression. Activity-dependent EGFP expression was not observed, and EGFP protein did not co-localize with native Egr1 protein.

Age-Related Intraneuronal Aggregation of Amyloid-β in Endosomes, Mitochondria, Autophagosomes, and Lysosomes.

This work provides new insight into the age-related basis of Alzheimer's disease (AD), the composition of intraneuronal amyloid (iAβ), and the mechanism of an age-related increase in iAβ in adult AD-model mouse neurons. A new end-specific antibody for Aβ45 and another for aggregated forms of Aβ provide new insight into the composition of iAβ and the mechanism of accumulation in old adult neurons from the 3xTg-AD model mouse. iAβ levels containing aggregates of Aβ45 increased 30-50-fold in neurons from young to old age and were further stimulated upon glutamate treatment.

Long-term Monocular Deprivation during Juvenile Critical Period Disrupts Binocular Integration in Mouse Visual Thalamus.

Study of the neural deficits caused by mismatched binocular vision in early childhood has predominantly focused on circuits in the primary visual cortex (V1). Recent evidence has revealed that neurons in mouse dorsolateral geniculate nucleus (dLGN) can undergo rapid ocular dominance plasticity following monocular deprivation (MD). It remains unclear, however, whether the long-lasting deficits attributed to MD during the critical period originate in the thalamus.

Reversibility of Age-related Oxidized Free NADH Redox States in Alzheimer's Disease Neurons by Imposed External Cys/CySS Redox Shifts.

Redox systems including extracellular cysteine/cystine (Cys/CySS), intracellular glutathione/oxidized glutathione (GSH/GSSG) and nicotinamide adenine dinucleotide reduced/oxidized forms (NADH/NAD) are critical for maintaining redox homeostasis. Aging as a major risk factor for Alzheimer's disease (AD) is associated with oxidative shifts, decreases in anti-oxidant protection and dysfunction of mitochondria. Here, we examined the flexibility of mitochondrial-specific free NADH in live neurons from non-transgenic (NTg) or triple transgenic AD-like mice (3xTg-AD) of different ages under an imposed extracellular Cys/CySS oxidative or reductive condition.

Global Metabolic Shifts in Age and Alzheimer's Disease Mouse Brains Pivot at NAD+/NADH Redox Sites.

Age and Alzheimer's disease (AD) share some common features such as cognitive impairments, memory loss, metabolic disturbances, bioenergetic deficits, and inflammation. Yet little is known on how systematic shifts in metabolic networks depend on age and AD. In this work, we investigated the global metabolomic alterations in non-transgenic (NTg) and triple-transgenic (3xTg-AD) mouse brain hippocampus as a function of age by using untargeted Ultrahigh Performance Liquid Chromatography-tandem Mass Spectroscopy (UPLC-MS/MS).

Age- and AD-related redox state of NADH in subcellular compartments by fluorescence lifetime imaging microscopy.

Nicotinamide adenine dinucleotide (reduced form: NADH) serves as a vital redox-energy currency for reduction-oxidation homeostasis and fulfilling energetic demands. While NADH exists as free and bound forms, only free NADH is utilized for complex I to power oxidative phosphorylation, especially important in neurons. Here, we studied how much free NADH remains available for energy production in mitochondria of old living neurons.

Deleting HDAC3 rescues long-term memory impairments induced by disruption of the neuron-specific chromatin remodeling subunit BAF53b.

Multiple epigenetic mechanisms, including histone acetylation and nucleosome remodeling, are known to be involved in long-term memory formation. Enhancing histone acetylation by deleting histone deacetylases, like HDAC3, typically enhances long-term memory formation. In contrast, disrupting nucleosome remodeling by blocking the neuron-specific chromatin remodeling subunit BAF53b impairs long-term memory.