Tourette disorder (TD) is a neurodevelopmental condition affecting approximately 0.3%-1% of children and adolescents. It is defined by motor and vocal tics but encompasses wide ranging phenotypes due to its complex genetic origins, involving hundreds of risk genes across various signaling pathways. Traditional animal models of TD have focused on circuit manipulation or neuron ablation strategies to investigate its underlying causes and associated brain changes. However, the recent identification of high-confidence risk genes has opened new possibilities for creating models that express the exact genetic variants associated with TD. This review discusses early attempts to model TD in rodents and highlights advancements in next-generation models with true construct validity through the expression of orthologous human mutations in high-confidence risk genes. Additionally, we examine the translational potential of integrating cognitive and sensorimotor approaches to evaluate TD-related phenotypes in rodents, including changes to reinforcement learning, habitual behavior, and incentive motivation.

Our internal sensory systems encode various gut-related sensations, such as hunger, feelings of fullness, and nausea. These internal feelings influence our eating behaviors and play a vital role in regulating energy balance. Among them, the neurological basis for nausea has been the least well characterized, which has hindered comprehension of the connection between these sensations. Single-cell sequencing, along with functional mapping, has brought clarity to the neural pathways of nausea involving the brainstem area postrema. In addition, the newly discovered nausea sensory signals have deepened our understanding of the area postrema in regulating feeding behaviors. Nausea has significant clinical implications, especially in developing drugs for weight loss and metabolism. This review summarizes recent research on the neural pathways of nausea, particularly highlighting their contribution to energy balance.

Neurons are equipped with microtubules of different stability with stable and dynamic domains often coexisting on the same microtubule. While dynamic microtubules undergo random transitions between disassembly and assembly, stable ones persist long enough to serve as platforms for tubulin-modifying enzymes (known as writers) that attach molecular components to the α- or β-tubulin subunits. The combination of these posttranslational modifications (PTMs) results in a "tubulin code," dictating the behavior of selected proteins (known as readers), some of which were shown to be crucial for neuronal function. Recent research has further highlighted that disturbances in tubulin PTMs can lead to neurodegeneration, sparking an emerging field of investigation with numerous questions such as whether and how tubulin PTMs can affect neurotransmission and synaptic plasticity and whether restoring balanced tubulin PTM levels could effectively prevent or mitigate neurodegenerative disease.

Subconscious breathing is generated by a network of brainstem nodes with varying purposes, like pacing breathing or patterning a certain breath phase. Decades of anatomy, pharmacology, and physiology studies have identified and characterized the system's fundamental properties that produce robust breathing, and we now have well-conceived computational models of breathing that are based on the detailed descriptions of neuronal connectivity, biophysical properties, and functions in breathing. In total, we have a considerable understanding of the brainstem breathing control circuit. But, in the last five years, the utilization of molecular and genetic approaches to study the neural subtypes within each node has led to a new era of breathing control circuit research that explains how breathing is integrated with more complex behaviors like speaking and running and how breathing is connected with other physiological systems and our state-of-mind. This review will describe the basic role of the key components of the brainstem breathing control circuit and then will highlight the new transformative discoveries that broaden our understanding of these breathing control brain areas. These new studies serve to illustrate the creativity and exciting future of breathing control research.

Astrocytes perform multiple functions in the nervous system, many of which are altered in neurodegenerative disorders. In this review, we explore shared astrocytic alterations across neurodegenerative disorders, including Alzheimer's disease, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, and frontotemporal lobe degeneration. Assessing recent datasets of single-nucleus RNA-sequencing of human brains, a theme emerges of common alterations in astrocyte state across disorders including in neuroinflammation, synaptic organization, metabolic support, and the cellular stress response. Immune pathways are upregulated by astrocytes across disorders and may exacerbate neurodegeneration. Dysregulated expression of synaptogenic factors could contribute to synaptic loss, while compromised metabolic support affects neuronal homeostasis. On the other hand, upregulated responses to cellular stress may represent a protective response of astrocytes and thus mitigate pathology. Understanding these shared responses offers insights into disease progression and provides potential therapeutic targets for various neurodegenerative disorders.

Corvids, readily adaptable across social and ecological contexts, successfully inhabit almost the entire world. They are seen as highly intelligent birds, and current research examines their cognitive abilities. Despite being songbirds with a complete 'song system', corvids have historically received less attention in studies of song production, learning, and perception compared to non-corvid songbirds. However, recent neurobiological studies have demonstrated that songbird vocal production and its neuronal representations are regularly influenced by environmental and cognitive factors. This opinion article discusses the literature on 'corvid song' before introducing other flexible vocal behaviors of corvids in both the wild and controlled laboratory studies. We suggest corvids with their flexible vocal control as promising model species to study the links between brain networks for cognition and vocalization. Studying corvid vocal flexibility and associated cognitive processes in both ecological and lab settings offers complementary insights, crucial for bridging the fields of cognition and birdsong.

Sleep problems occur more frequently in individuals with autism spectrum disorder (ASD) than in typically developing individuals, and recent studies support a genetic link between ASD and sleep disturbances. However, it remains unclear how sleep problems may be mechanistically connected to ASD phenotypes. A longstanding hypothesis posits that an imbalance between excitatory and inhibitory (E/I) signaling in the brain underlies the behavioral characteristics of ASD. In recent years, emerging evidence has shown that regulation of the E/I ratio is coupled to sleep/wake states in wild-type animal models. In this review, we will explore the idea of altered E/I regulation over the sleep/wake cycle as a mechanism bridging sleep disruption and behavioral phenotypes in ASD.

Every species in the animal kingdom that learns, also forgets. Despite this balance between learning and forgetting, most neuroscientific explorations of memory have focused on how learning occurs, with recent studies identifying engrams as putative biological substrates for memory. Here we review an emerging literature that, in contrast, explores how our brains forget. These studies reveal that forgetting engages a broad collection of mechanisms that function to reduce engram accessibility. However, changes in accessibility emerge on vastly different timescales. At short timescales, forgetting is modulated by fluctuations in brain states that alter engram accessibility in a moment-to-moment fashion. In the intermediate- and long-term, forgetting depends, in part, on mechanisms that rewire engrams, rendering them gradually harder to access. Viewed this way, forgetting encompasses a family of plasticity mechanisms that modulate engram accessibility, perhaps in order to prioritize those memories that are most timely or relevant to the situation at hand.

Sensing our internal environment, or interoception, is essential under physiologic circumstances, such as controlling food intake, and under pathophysiologic circumstances, often triggering abdominal pain. The sensory neurons that innervate the gastrointestinal (GI) tract to mediate interoception originate in two separate parts of the peripheral nervous system: the spinal sensory neurons, whose cell bodies reside in the dorsal root ganglia (DRG), and the vagal sensory neurons, whose cell bodies reside in the nodose ganglia. While the vagal sensory neurons have been extensively studied for their roles in interoception, the roles of the DRG sensory neurons in internal gut sensing are only beginning to be uncovered. Here, we review the recent advances in understanding the diverse properties and functions of gut-innervating DRG sensory neurons and highlight the many unknowns with regards to this understudied population in regulating interoception.

Trillions of synapses in the human brain enable thought and behavior. Synaptic connections must be established and maintained, while retaining dynamic flexibility to respond to experiences. These processes require active remodeling of the synapse to control the composition and integrity of proteins and organelles. Macroautophagy (hereafter, autophagy) provides a mechanism to edit and prune the synaptic proteome. Canonically, autophagy has been viewed as a homeostatic process, which eliminates aged and damaged proteins to maintain neuronal survival. However, accumulating evidence suggests that autophagy also degrades specific cargoes in response to neuronal activity to impact neuronal transmission, excitability, and synaptic plasticity. Here, we will discuss the diverse roles, regulation, and mechanisms of neuronal autophagy in synaptic function and contributions from glial autophagy in these processes.

Astrocytes are the most prevalent glial cells of the brain and mediate vital roles in the development and function of the nervous system. Astrocytes, along with microglia, also play key roles in initiating inflammatory immune responses following brain injury, stress, or disease-related triggers. While these glial immune responses help contain and resolve cellular damage to the brain, dysregulation of astrocyte activity can in some cases amplify inflammation and worsen impact on neural tissue. As nonexcitable cells, astrocytes excitability is regulated primarily by Ca signals that control key functions such as gene expression, release of inflammatory mediators, and cell metabolism. In this review, we examine the molecular and functional architecture of Ca signaling networks in astrocytes and their impact on astrocyte effector functions involved in inflammation and immunity.

The axon initial segment (AIS) is a specialized domain that maintains neuronal polarity and is the site of action potential generation, both of which underlie the neuron's ability to send and receive signals. Disruption of the AIS leads to a loss of neuronal polarity, altered neuronal signaling, and an array of neurological disorders. Therefore, understanding how the AIS forms and functions is a central question in cellular neuroscience that is essential to understanding neuronal physiology. Decades of study have identified many molecular components and mechanisms at the AIS. Recently, endocytosis at the AIS has been identified to function in both maintaining neuronal polarity and in mediating AIS plasticity through its ability to dynamically remodel the plasma membrane composition. This review discusses the emerging evidence for the roles of endocytosis in regulating AIS function and structural insights into how endocytosis can occur at the AIS.

Critical periods are brief windows of heightened neural circuit plasticity that allow circuits to permanently reset their structure and function to facilitate robust organismal behavior. Understanding the cellular and molecular mechanisms that instruct critical period timing is of broad clinical interest, as altered developmental plasticity is linked to multiple neurodevelopmental disorders. While intrinsic, neuronal mechanisms shape both neural circuit remodeling and critical period timing, recent data indicate that signaling from astrocytes and surrounding glia can both promote and limit critical period plasticity. In this short review, we discuss recent breakthroughs in our understanding of astrocytes in critical period plasticity and highlight pioneering work in Drosophila.

GABAergic synaptic inhibition controls circuit function by regulating neuronal plasticity, excitability, and firing. To achieve these goals, inhibitory synapses themselves undergo several forms of plasticity via diverse mechanisms, strengthening and weakening phasic inhibition in response to numerous activity-induced stimuli. These mechanisms include changing the number and arrangement of functional GABARs within the inhibitory postsynaptic domain (iPSD), which can profoundly regulate inhibitory synapse strength. Here, we explore recent advances in our molecular understanding of inhibitory postsynaptic plasticity, with a focus on modulation of the trafficking, protein-protein interactions, nanoscale-organization, and posttranscriptional regulation of GABARs and iPSD proteins. What has emerged is a complex mechanistic picture of how synaptic inhibition is controlled, with critical ramifications for cognition under typical and pathogenic conditions.

Autism spectrum disorders (ASD) are substantially heterogeneous neuropsychiatric conditions with over a thousand associated genetic factors and various environmental influences, such as infection and nutrition. Additionally, males are four times more likely than females to be affected. This heterogeneity underscores the need to uncover common molecular features within ASD. Recent studies have revealed interactions among genetic predispositions, environmental factors, and sex that may be critical to ASD etiology. This review focuses on emerging evidence for the impact of nutrients-particularly zinc and amino acids-on ASD, as demonstrated in mouse models and human studies. These nutrients have been shown to influence synaptic signaling, dendritic spine formation, and behaviors linked to autism. Furthermore, sex-based differences in nutritional requirements, especially for zinc and amino acids, may contribute to the observed male bias in autism, indicating that interactions between nutrients and genetic factors could be integral to understanding and potentially mitigating ASD symptoms.

The ANK2 gene, encoding ankyrin-B, is a high-confidence risk factor for neurodevelopmental disorders (NDDs). Evidence from exome sequencing studies have repeatedly implicated rare variants in ANK2 in autism spectrum disorder. Recently, the functions of ankyrin-B isoforms on neuronal phenotypes have been investigated using a number of techniques including electrophysiology, proteomic screens and behavioral analysis using animal models with loss of distinct Ank2 isoforms or with targeted loss of Ank2 in different cell types and time points during brain development. ANK2 variants and their pathophysiology could provide valuable insights into the molecular mechanisms underlying NDDs. In this review, we focus on recently reported studies to help understand the pathological mechanisms of ANK2 loss and how it may facilitate the development of treatments for NDDs in the future.

Cryo-electron tomography (cryo-ET) visualizes natively preserved cellular ultrastructure at molecular resolution. Recent developments in sample preparation workflows and image processing tools enable growing applications of cryo-ET in cellular neurobiology. As such, cryo-ET is beginning to unravel the in situ macromolecular organization of neurons using samples of increasing complexity. Here, we highlight advances in cryo-ET technology and review its recent use to study neuronal architecture and its alterations under disease conditions.

A limiting step of neuronal circuit formation is the extensive migration of interneurons from their birthplace to populate territories formed by excitatory neurons. Interneuron dynamics in the developing brain culminates with the organization of interneuron subtypes in specific configurations within layers of brain tissue. Decoding the logic behind these configurations is still matter of passionate debate. Do interneurons follow a sketched program from the progenitor state or is this organization sculpted from intricate cellular interactions? How do interneurons select interacting partners? How does interneuron diversity emerge? New technologies and access to brain tissue from different species are allowing us to reconstruct stone by stone, the convoluted path leading to the formation of neuronal cell assemblies made of excitatory and inhibitory neurons. The most recent research highlights that interneuron subtype circuit integration needs to be assessed case by case. Here, I highlight the need to keep delving into the complexities of interneuron interaction with their environment during development to accomplish this Herculean task.

Motor neurons have highly diverse anatomical, functional and molecular features, and differ significantly in their susceptibility in disease. Extraocular motor neurons, residing in the oculomotor, trochlear and abducens cranial nuclei (nIII, nIV and nVI), control eye movements. Recent work has begun to clarify the developmental mechanisms by which functional diversity among extraocular motor neurons arises. However, we know little about the role and consequences of extraocular motor neuron diversity in eye movement control. Here, we highlight recent work investigating the anatomical, functional and molecular features of extraocular motor neurons. Further, we frame hypotheses where studying ocular motor circuits in the larval zebrafish is poised to illuminate the consequences of motor neuron diversity for behavior.

Neurodevelopmental disorders are a heterogenous group of brain disorders impacting cognitive, adaptive, motor, and speech language development. With advancements in diagnostics an increasing number of causative genes are discovered, including synaptic genes. The calcium calmodulin dependent protein kinase type 2 (CAMK2) family is the most abundant kinase family in the synapse and has recently been established to cause NDD, with a growing number of unrelated NDD-individuals who carry pathogenic variations in one of the four CAMK2 genes. However, there is still much to learn about the specific phenotypic manifestations per CAMK2 paralog and per variant type, including the mechanism of how variants in these genes impact CAMK2 protein and synaptic functioning, and result in neurodevelopmental disorders. This review provides an overview of all CAMK2 cases published to date and reveals first genotype-phenotype correlations that can serve as a starting point to explain CAMK2 related symptoms, offering direction for future research.

Cyclic AMP (cAMP) is a key regulator of synaptic function and is dysregulated in both neurodevelopmental (NDD) and neurodegenerative disorders. Due to the ease of diffusion and promiscuity of downstream effectors, cAMP signaling is restricted within spatiotemporal domains to localize activation. Among the best-studied mechanisms is the feedback inhibition of cAMP-dependent protein kinase (PKA) activity by phosphodiesterases 4 (PDE4s) at synapses controlling neuronal plasticity, which is largely regulated by PDE4D. In fact, genetic variants in genes for multiple PKA subunits and PDE4D lead to NDDs. Here, we discuss the rationale for choosing PDE4D as a candidate for the design of selective allosteric inhibitors and the recent advances in clinical trials. These new compounds improve cognitive function in preclinical animal models due to improved selectivity and more physiological inhibition of the active enzyme. We also discuss opportunities for better understanding of PDE4D function in general, and for the development of next-generation inhibitors.