Genetic variants in DDX53 contribute to autism spectrum disorder associated with the Xp22.11 locus.

Autism spectrum disorder (ASD) exhibits an ∼4:1 male-to-female sex bias and is characterized by early-onset impairment of social/communication skills, restricted interests, and stereotyped behaviors. Disruption of the Xp22.11 locus has been associated with ASD in males.

A sensitive period for the development of episodic-like memory in mice.

Episodic-like memory is a later-developing cognitive function supported by the hippocampus. In mice, the formation of extracellular perineuronal nets in subfield CA1 of the dorsal hippocampus controls the emergence of episodic-like memory during the fourth postnatal week (Ramsaran et al., 2023).

Stress disrupts engram ensembles in lateral amygdala to generalize threat memory in mice.

Stress induces aversive memory overgeneralization, a hallmark of many psychiatric disorders. Memories are encoded by a sparse ensemble of neurons active during an event (an engram ensemble). We examined the molecular and circuit processes mediating stress-induced threat memory overgeneralization in mice.

Dentate gyrus ensembles gate context-dependent neural states and memory retrieval.

Memories of events are linked to the contexts in which they were encoded. This contextual linking ensures enhanced access to those memories that are most relevant to the context at hand, including specific associations that were previously learned in that context. This principle, referred to as encoding specificity, predicts that context-specific neural states should bias retrieval of particular associations over others, potentially allowing for the disambiguation of retrieval cues that may have multiple associations or meanings.

Higher-order interactions between hippocampal CA1 neurons are disrupted in amnestic mice.

Across systems, higher-order interactions between components govern emergent dynamics. Here we tested whether contextual threat memory retrieval in mice relies on higher-order interactions between dorsal CA1 hippocampal neurons requiring learning-induced dendritic spine plasticity. We compared population-level Ca2 transients as wild-type mice (with intact learning-induced spine plasticity and memory) and amnestic mice (TgCRND8 mice with high levels of amyloid-β and deficits in learning-induced spine plasticity and memory) were tested for memory.

Engrams.

Frankland et al. provide a history of research on engrams and their relationship to memory processes, highlighting new technologies that have allowed careful dissection of engrams and their function.

Comparing behaviours induced by natural memory retrieval and optogenetic reactivation of an engram ensemble in mice.

Memories are thought to be stored within sparse collections of neurons known as engram ensembles. Neurons active during a training episode are allocated to an engram ensemble ('engram neurons'). Memory retrieval is initiated by external sensory or internal cues present at the time of training reactivating engram neurons.

Neurogenesis-dependent remodeling of hippocampal circuits reduces PTSD-like behaviors in adult mice.

Post-traumatic stress disorder (PTSD) is a hypermnesic condition that develops in a subset of individuals following exposure to severe trauma. PTSD symptoms are debilitating, and include increased anxiety, abnormal threat generalization, and impaired extinction. In developing treatment strategies for PTSD, preclinical studies in rodents have largely focused on interventions that target post-encoding memory processes such as reconsolidation and extinction.

Reactivation of encoding ensembles in the prelimbic cortex supports temporal associations.

Fear conditioning is encoded by strengthening synaptic connections between the neurons activated by a conditioned stimulus (CS) and those activated by an unconditioned stimulus (US), forming a memory engram, which is reactivated during memory retrieval. In temporal associations, activity within the prelimbic cortex (PL) plays a role in sustaining a short-term, transient memory of the CS, which is associated with the US after a temporal gap. However, it is unknown whether the PL has only a temporary role, transiently representing the CS, or is part of the neuronal ensembles that support the retrieval, i.

Excitability mediates allocation of pre-configured ensembles to a hippocampal engram supporting contextual conditioned threat in mice.

Little is understood about how engrams, sparse groups of neurons that store memories, are formed endogenously. Here, we combined calcium imaging, activity tagging, and optogenetics to examine the role of neuronal excitability and pre-existing functional connectivity on the allocation of mouse cornu ammonis area 1 (CA1) hippocampal neurons to an engram ensemble supporting a contextual threat memory. Engram neurons (high activity during recall or TRAP2-tagged during training) were more active than non-engram neurons 3 h (but not 24 h to 5 days) before training.

Nonsynonymous Mutations in Intellectual Disability and Autism Spectrum Disorder Gene PTCHD1 Disrupt -Glycosylation and Reduce Protein Stability.

has been implicated in Autism Spectrum Disorders (ASDs) and/or intellectual disability, where copy-number-variant losses or loss-of-function coding mutations segregate with disease in an X-linked recessive fashion. Missense variants of have also been reported in patients. However, the significance of these mutations remains undetermined since the activities, subcellular localization, and regulation of the PTCHD1 protein are currently unknown.

Examining memory linking and generalization using scFLARE2, a temporally precise neuronal activity tagging system.

How memories are organized in the brain influences whether they are remembered discretely versus linked with other experiences or whether generalized information is applied to entirely novel situations. Here, we used scFLARE2 (single-chain fast light- and activity-regulated expression 2), a temporally precise tagging system, to manipulate mouse lateral amygdala neurons active during one of two 3 min threat experiences occurring close (3 h) or further apart (27 h) in time. Silencing scFLARE2-tagged neurons showed that two threat experiences occurring at distal times are dis-allocated to orthogonal engram ensembles and remembered discretely, whereas the same two threat experiences occurring in close temporal proximity are linked via co-allocation to overlapping engram ensembles.

Neuronal transcription of autism gene PTCHD1 is regulated by a conserved downstream enhancer sequence.

Patched domain-containing 1 (PTCHD1) is a well-established susceptibility gene for autism spectrum disorder (ASD) and intellectual disability (ID). Previous studies have suggested that alterations in the dosage of PTCHD1 may contribute to the etiology of both ASD and ID. However, there has not yet been a thorough investigation regarding mechanisms that regulate PTCHD1 expression.

A shift in the mechanisms controlling hippocampal engram formation during brain maturation.

The ability to form precise, episodic memories develops with age, with young children only able to form gist-like memories that lack precision. The cellular and molecular events in the developing hippocampus that underlie the emergence of precise, episodic-like memory are unclear. In mice, the absence of a competitive neuronal engram allocation process in the immature hippocampus precluded the formation of sparse engrams and precise memories until the fourth postnatal week, when inhibitory circuits in the hippocampus mature.

Examining the engram encoding specificity hypothesis in mice.

According to the encoding specificity hypothesis, memory is best recalled by retrieval cues that overlap with training cues. Human studies generally support this hypothesis. However, memories are thought to be stored in neuronal ensembles (engrams), and retrieval cues are thought to reactivate neurons in an engram to induce memory recall.

Alcohol Dependence Modifies Brain Networks Activated During Withdrawal and Reaccess: A c-Fos-Based Analysis in Mice.

Background: High-level alcohol consumption causes neuroplastic changes in the brain that promote pathological drinking behavior. Some of these changes have been characterized in defined brain circuits and cell types, but unbiased approaches are needed to explore broader patterns of adaptations.

Methods: We used whole-brain c-Fos mapping and network analysis to assess patterns of neuronal activity during alcohol withdrawal and following reaccess in a well-characterized model of alcohol dependence.

Formation and fate of an engram in the lateral amygdala supporting a rewarding memory in mice.

Memories allow past experiences to guide future decision making and behavior. Sparse ensembles of neurons, known as engrams, are thought to store memories in the brain. Most previous research has focused on engrams supporting threatening or fearful memories where results show that neurons involved in a particular engram ("engram neurons") are both necessary and sufficient for memory expression.

Homeostatic coordination and up-regulation of neural activity by activity-dependent myelination.

Activity-dependent myelination (ADM) is a fundamental dimension of brain plasticity through which myelin changes as a function of neural activity. Mediated by structural changes in glia, ADM notably regulates axonal conduction velocity. Yet, it remains unclear how neural activity impacts myelination to orchestrate the timing of neural signalling, and how ADM shapes neural activity.

Toxoplasma infection in male mice alters dopamine-sensitive behaviors and host gene expression patterns associated with neuropsychiatric disease.

During chronic infection, the single celled parasite, Toxoplasma gondii, can migrate to the brain where it has been associated with altered dopamine function and the capacity to modulate host behavior, increasing risk of neurocognitive disorders. Here we explore alterations in dopamine-related behavior in a new mouse model based on stimulant (cocaine)-induced hyperactivity. In combination with cocaine, infection resulted in heightened sensorimotor deficits and impairment in prepulse inhibition response, which are commonly disrupted in neuropsychiatric conditions.