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The rates of onset for several forms of psychopathology peak during adolescence, which coincides with the refinement of brain circuitry attuned to expanding social-contextual interactions, stressors, and settings. While some adolescents experience mental health difficulties, most do not develop significant problems. Conceptual work suggests that brain-based individual differences in adolescents' neurobiological susceptibility to their social contexts play a role in the development of psychopathology and well-being. In this article, I summarize evidence supporting the idea that individual differences in brain structure and function moderate the relation between adolescents' social-contextual experiences and psychopathology. I discuss why this approach is important in developmental research designed to identify adolescents at greatest risk for psychopathology or poised for positive outcomes, as well as those who may benefit most from intervention.

Manmade chemicals with endocrine disrupting properties are pervasive in the environment and are present in the bodies of humans and in wildlife. As thyroid hormones (THs) control normal brain development, and maternal hypothyroxinemia is associated with neurological impairments in children, chemicals that interfere with TH signaling are of considerable concern for children's health. However, identifying thyroid disrupting chemicals (TDCs) in vivo is largely based on serum tetraiodothyronine (T4) measures in rats, which may be inadequate to assess TDCs with disparate mechanisms of action. Neither are detection of serum hormone deficits alone sufficient to evaluate the potential neurotoxicity of TDCs. In this review we describe two neurodevelopmental processes that are dependent on TH action, neuronal migration and maturation of GABAergic interneurons. We discuss how interruption of these processes may contribute to abnormal brain circuitry following developmental TH insufficiency, and thus may also be affected by TDCs. Finally, we outline existing issues in evaluating the developmental neurotoxicity TDCs in rodent models, and the strengths and limitations of current approaches to their regulation. Given the state of the science, it is clear that an enhanced understanding of how THs affect brain development will lead to refined toxicity testing, reducing uncertainty and improve our ability to protect children's health.

The ability to rapidly arouse from sleep is important for survival. However, increased arousals in patients with sleep apnea and other disorders prevent restful sleep, and contribute to cognitive, metabolic and physiologic dysfunction [1, 2]. Little is currently known about which neural systems mediate these brief arousals, hindering the development of treatments which restore normal sleep. The basal forebrain (BF) receives inputs from many nuclei of the ascending arousal system including the brainstem parabrachial neurons which promote arousal in response to elevated blood carbon dioxide levels, as seen in sleep apnea [3]. Optical inhibition of the terminals of parabrachial neurons in the BF impairs cortical arousals to hypercarbia [4], but which BF cell types mediate cortical arousals in response to hypercarbia or other sensory stimuli is unknown. Here we tested the role of BF parvalbumin (PV) neurons in arousal using optogenetic techniques in mice. Optical stimulation of BF-PV neurons produced rapid transitions to wakefulness from non-rapid-eye movement (NREM) sleep but did not affect REM-wakefulness transitions. Unlike previous studies of BF glutamatergic and cholinergic neurons, arousals induced by stimulation of BF-PV neurons were brief and only slightly increased total wake time, reminiscent of clinical findings in sleep apnea [5, 6]. Bilateral optical inhibition of BF-PV neurons increased the latency to arousal produced by exposure to hypercarbia or auditory stimuli. Thus, BF-PV neurons are an important component of the brain circuitry which generates brief arousals from sleep in response to stimuli which may indicate physiological dysfunction or danger to the organism.

The quantity and quality of the language input that infants receive from their caregivers affects their future language abilities; however, it is unclear how variation in this input relates to preverbal brain circuitry. The current study investigated the relation between naturalistic language input and the functional connectivity (FC) of language networks in human infancy using resting-state functional magnetic resonance imaging (rsfMRI). We recorded the naturalistic language environments of five- to eight-month-old male and female infants using the Linguistic ENvironment Analysis (LENA) system and measured the quantity and consistency of their exposure to adult words (AWs) and adult–infant conversational turns (CTs). Infants completed an rsfMRI scan during natural sleep, and we examined FC among regions of interest (ROIs) previously implicated in language comprehension, including the auditory cortex, the left inferior frontal gyrus (IFG), and the bilateral superior temporal gyrus (STG). Consistent with theory of the ontogeny of the cortical language network (Skeide and Friederici, 2016), we identified two subnetworks posited to have distinct developmental trajectories: a posterior temporal network involving connections of the auditory cortex and bilateral STG and a frontotemporal network involving connections of the left IFG. Independent of socioeconomic status (SES), the quantity of CTs was uniquely associated with FC of these networks. Infants who engaged in a larger number of CTs in daily life had lower connectivity in the posterior temporal language network. These results provide evidence for the role of vocal interactions with caregivers, compared with overheard adult speech, in the function of language networks in infancy.

Play is a complex social behavior that is highly conserved across mammals. In most species, males engage in more frequent and vigorous play as juveniles than females, which reflects subtle yet impactful sex differences in brain circuitry and development. In this protocol, we describe a behavioral testing paradigm to assess social play in male and female juvenile rats. We highlight the behavior scoring criteria for distinguishing rough-and-tumble play from other play-related social behaviors. By analyzing both sexes, play behavior can be leveraged as a powerful tool to understand the sex-specific development and expression of social behavior.

Early-life experience can modulate risk versus resilience to emotional and cognitive disorders in adulthood. This suggests that there is a particularly sensitive period early in life, during which beneficial or adverse events can cause a later propensity toward stress resilience or vulnerability, respectively. Most early-life experiences are generated from signals received from the primary caregiver, and perturbations in these signals can program stress-related behaviors throughout life. These maternal signals cause lasting changes in brain circuitry and function, including networks associated with learning and memory, and with emotional and stress responses. Underlying these changes in brain circuits are transcriptional and epigenetic mechanisms. These molecular changes are instigated by early-life experiences and set in motion a signaling cascade that can determine resilience or vulnerabilities in adulthood.

Clinical testing of the awake patient during or prior to functional neurosurgical procedures such as deep brain stimulator (DBS) placement, focused ultrasound (FUS), or epilepsy surgeries is a valuable tool to verify that the appropriate target has been engaged for purposes of improving symptoms. This testing also serves to identify potential adverse effects of surgical therapy that may limit efficacy or lead to poor outcomes. The treating clinician should be familiar with both the regional anatomy and brain circuitry involved in these diseases states, as well as the testing sequences, parameters, and interpretation of results in order to make appropriate therapeutic decisions for individual patients. This chapter reviews testing patients with movement and neuropsychiatric disorders during DBS or FUS procedures and patients with epilepsy prior to surgical intervention.

How an animal responds to environmental stressors and threats is essential for survival. These responses are governed through an interconnected circuit in the brain dubbed the limbic system. Three main structures of the limbic system are the amygdala, bed nucleus of the stria terminalis (BNST), and hypothalamus. Together these structures define a central stress-threat circuit. This chapter describes the most up to date knowledge of how these structures function in regulating responses to stressors and how each of these structures is formed from embryonic development. This knowledge of the underlying biology of these regions is essential to design rational therapeutic approaches for conditions, such as post-traumatic stress disorder (PTSD) that are characterized by dysregulation of the stress-threat system. In this chapter, we also describe the critical unanswered questions in the field of stress-threat research and potential future research directions.

Background and purpose: Neurobiological changes in memory processes seem to play a role in the pathophysiology of post-traumatic stress disorder (PTSD). Memory itself is influenced by PTSD, too. Histone deacetylase inhibitors (HDAIs) have shown promising results in the extinction of fear-related memories in animals and hence they seem to be important for the treatment of PTSD. Data are scarce about the effect of HDAIs in spatial memory formation/extinction in PTSD models. The main goal of the present work is to find the effect of sodium butyrate (NaBu), as an HDAI, on spatial memory and spatial memory extinction in rats exposed to single prolonged stress procedure (SPS). Experimental approach: Different doses of NaBu were administered subcutaneously for 7 days in different groups of rats after SPS procedure. Learning, memory, and extinction of memory were evaluated in the Morris water maze test of spatial memory in 6 consecutive days. Findings / Results: The results show that NaBu (0.5 mg/kg) alleviates impaired learning and memory in SPS rats. It also facilitates the extinction of newly formed memory in the animals. Conclusion and implications: Our data suggest that the administration of HDAIs after a traumatic experience can prevent the aversive effects of SPS on spatial memory. It also reinforces the notion that extinction of spatial memory involves the same or similar brain circuitry that is involved in the extinction of fear memories in PTSD patients.

Pain-related fear and avoidance are increasingly demonstrated to play an important role in adult and childhood chronic pain. The Fear of Pain Questionnaire for Children (FOPQC) is a 24-item measure of pain-related fear-avoidance in youth that has demonstrated good indices of reliability and validity, treatment responsiveness, and associations with brain circuitry alterations. This study describes the development and psychometric examination of the FOPQC-SF, a short form of the original measure. We selected 10 items for the short form that best represented the content and 2-factor (fear and avoidance) structure of the original measure from a cohort of 613 youth (Mage = 14.7 years) with chronic pain. Next, confirmatory factor analyses from a second sample of 526 youth (Mage = 14.7 years) with chronic pain who completed the FOPQC-SF supported the original 2-factor model but indicated that one item should be moved to the avoidance subscale. The FOPQC-SF demonstrates strong internal consistency and moderate-to-strong construct and criterion validity. The 3-month test-retest reliability estimates (N = 94) were strong, and there was preliminary evidence of responsivity to change. To aid integration into intervention trials and clinical practice, we provide clinical reference points and a criterion to assess reliable change. The short form could be used for rapid identification of pain-related fear and avoidance in youth during clinic evaluations, and is optimized for clinical registries.

Parkinson's disease (PD) is a debilitating neurodegenerative disorder, for which people above the age of 60 show an increased risk. Although there has been great advancement in understanding the disease-related abnormalities in brain circuitry and development of symptomatic treatments, a cure for PD remains elusive. The discovery of PD associated gene mutations and environmental toxins have yielded animal models of the disease. These models could recapitulate several key aspects of PD, and provide more insights into the disease pathogenesis. They have also revealed novel aspects of the disease mechanism including noncell autonomous events and spreading of pathogenic protein species across the brain. Nevertheless, none of these models so far can comprehensively represent all aspects of the human disease. While the field is still searching for the perfect model system, recent developments in stem cell biology have provided a new dimension to modelling PD, especially doing it in a patient-specific manner. In the current review, we attempt to summarize the key findings in the areas discussed above, and highlight how the core PD pathology distinguishes itself from other neurodegenerative disorders while also resembling them in many aspects.

The human brain comprises a multiscale network with multiple levels of organization. Neurons with dendritic and axonal connections form the microscale fabric of brain circuitry, and macroscale brain regions and white matter connections form the infrastructure for system-level brain communication and information integration. In this review, we discuss the emerging trend of multiscale neuroscience, the multidisciplinary field that brings together data from these different levels of nervous system organization to form a better understanding of between-scale relationships of brain structure, function, and behavior in health and disease. We provide a broad overview of this developing field and discuss recent findings of exemplary multiscale neuroscience studies that illustrate the importance of studying cross-scale interactions among the genetic, molecular, cellular, and macroscale levels of brain circuitry and connectivity and behavior. We particularly consider a central, overarching goal of these multiscale neuroscience studies of human brain connectivity: to obtain insight into how disease-related alterations at one level of organization may underlie alterations observed at other scales of brain network organization in mental disorders. We conclude by discussing the current limitations, challenges, and future directions of the field.

Alcohol use disorder (AUD) is a chronic relapsing condition that represents a significant public health concern. Pharmacological treatment development for AUD is a top research priority and many studies are being conducted to evaluate potential AUD treatments. Understanding the brain circuitry impacted by addiction is crucial for the development of efficacious pharmacological interventions. These neuroadaptations can be probed non-invasively using functional magnetic resonance neuroimaging (fMRI). fMRI may be an effective tool to identify biomarkers for AUD pharmacotherapies, evaluating changes associated with pharmacological treatment. Thus, the present qualitative review of the literature focuses on the role of fMRI as a tool for medications development for AUD. The aim of this review was to assemble research across a range of fMRI paradigms to study the effectiveness of pharmacological treatments of adult AUD. First, we present a qualitative review of fMRI AUD pharmacotherapy studies, differentiating studies based on their dosing regimen. Second, we provide recommendations for the field to improve the use of fMRI as a biomarker for AUD pharmacotherapy.

SummaryA central aim, from basic neuroscience to psychiatry, is to resolve how genes control brain circuitry and behavior. This is experimentally hard, since most brain functions and behaviors are controlled by multiple genes. In low throughput, one gene at a time, experiments, it is therefore difficult to delineate the neural circuitry through which these sets of genes express their behavioral effects. The increasing amount of publicly available brain and genetic data offers a rich source that could be mined to address this problem computationally. However, most computational approaches are not tailored to reflect functional synergies in brain circuitry accumulating within sets of genes. Here, we developed an algorithm that fuses gene expression and connectivity data with functional genetic meta data and exploits such cumulative effects to predict neuroanatomical maps for multigenic functions. These maps recapture known functional anatomical annotations from literature and functional MRI data. When applied to meta data from mouse QTLs and human neuropsychiatric databases, our method predicts functional maps underlying behavioral or psychiatric traits. We show that it is possible to predict functional neuroanatomy from mouse and human genetic meta data and provide a discovery tool for high throughput functional exploration of brain anatomyin silico.

Drug addiction can be conceptualized at a basic level as maladaptive learning and memory. Addictive substances elicit changes in brain circuitry involved in reward, cognition, and emotional state, leading to the formation and persistence of strong drug-associated memories that lead to craving and relapse. Recently, perineuronal nets (PNNs), extracellular matrix (ECM) structures surrounding neurons, have emerged as regulators of learning, memory, and addiction behaviors. PNNs do not merely provide structural support to neurons but are dynamically remodeled in an experience-dependent manner by metalloproteinases. They function in various brain regions through constituent proteins such as brevican that are implicated in neural plasticity. Understanding the function of PNN components in memory processes may lead to new therapeutic approaches to treating addiction.

BACKGROUND Disrupted sleep, including daytime hypersomnolence, is a core symptom reported by primary brain tumor patients and often manifests after radiotherapy. The biological mechanisms driving cranial radiation-induced hypersomnolence (C-RIH) remain unclear but we hypothesize this may result from damage to neural circuits controlling sleep behavior. We developed a mouse model of C-RIH to explore the impact of radiation on the brain: examining region-specific differences in acute DNA damage response and neuroanatomic structure. METHODS Mice received whole brain radiation then behaviors were monitored using PhenoTyper® cages to determine optimal dose and long-term effects. To test short-term neurologic effects, brains were collected 1hr post-radiation then stained for γH2AX, a signal for DNA damage. Long-term effects were quantified 1-month post-treatment using neuroimaging to determine brain volume and T1 mapping changes in regions associated with sleep, circadian rhythms, and cognition. RESULTS Mice displayed decreased general activity and increased daytime sleep in a dose-dependent and sustained manner. Histologic staining demonstrated that DNA damage following radiation varies across the brain, with homeostatic sleep regions and cognitive regions expressing higher levels of γH2AX than the circadian suprachiasmatic nucleus. These findings were supported by in vitro studies comparing radiation effects in SCN and cortical astrocytes using both trypan blue (F(1,18)=235.937, p< 0.001) and clonogenic assays (F(1,24)=40.796, < 0.001). Brain volumes were significantly smaller in irradiated than sham animals in the hippocampus (t(4)=3.833, p=0.019) and the pontine central grey (t(4)=3.504, p=0.025). T1 maps also showed significant changes in relaxation times in many cognitive regions but not sleep or circadian areas. CONCLUSIONS These findings suggest that the homeostatic sleep region and cognitive circuits are vulnerable to radiation and may be relevant to the development of treatment plans in patients. We plan to introduce intracranial tumor to the model to evaluate the impact of timing of treatment and C-RIH on survival.

Reading is a uniquely human skill, learned through extensive experience during childhood, with literacy becoming widespread only in the past few hundred years. Consequently, the neural circuitry underlying language could not have evolved to have circuitry genetically predefined for reading; this is unlike other expert skills such as face recognition, which can be seen in some of our evolutionary ancestors. Therefore, understanding the nature of the reading circuit strikes at the heart of the nature versus nurture debate about how expert skills shape, and are shaped by, brain circuitry. The PNAS article by Lerma-Usabiaga et al. (1) focuses on understanding the specialization of a particular brain territory, the left ventral occipitotemporal cortex (vOTC), known to be critical for visual word recognition. The study uses a combination of magnetic resonance imaging (MRI) and behavioral methods to carefully dissect two functionally and structurally distinct regions located within the vOTC that contribute to reading. Lerma-Usabiaga et al. (1) were motivated by previous studies that have used functional MRI to localize the “visual word form area” (VWFA). Conceptually, the VWFA is a brain region within the left vOTC that responds preferentially to printed words and word-like stimuli. This orthographic selectivity emerges with the acquisition of literacy, indicating that reading experience tunes this region for skilled reading (2). Indeed, individuals with poorer reading ability exhibit reduced selectivity in the vOTC (3), and damage in adulthood causes acquired alexia, in which printed words can no longer be recognized automatically (4). While researchers agree on these broad facts about the VWFA, they disagree on the precise location of the VWFA and its specific role in reading (4⇓–6). These disagreements could arise because different types of stimulus comparisons weight differentially for perceptual versus linguistic aspects of visual word recognition. Thus, like the proverbial men … [↵][1]1To whom correspondence should be addressed. Email: fiez{at}pitt.edu. [1]: #xref-corresp-1-1

Neurobehavioral impairment associated with COVID-19 infection has been recently documented in the literature. COVID-19 infection has also been associated with an increased risk for developing psychiatric symptoms, including rare reports on psychosis. We report a case of a 46-year-old male with no significant medical, family, and psychiatric history admitted to the hospital with COVID-19-related psychosis. Possible contributory factors for his condition are discussed, including the relationship between infections and the brain circuitry, inadvertent iatrogenic effects of pharmaceuticals used to manage COVID-19, as well as diathesis-stress associated with the tribulation of the prevailing pandemic.

This article outlines the fundamental brain mechanisms that control sleep-wake patterns and reviews how pathologic changes in these control mechanisms contribute to common sleep disorders.Discrete but interconnected clusters of cells located within the brainstem and hypothalamus comprise the circuits that generate wakefulness, non-rapid eye movement (non-REM) sleep, and REM sleep. These clusters of cells use specific neurotransmitters, or collections of neurotransmitters, to inhibit or excite their respective sleep- and wake-promoting target sites. These excitatory and inhibitory connections modulate not only the presence of wakefulness or sleep, but also the levels of arousal within those states, including the depth of sleep, degree of vigilance, and motor activity. Dysfunction or degeneration of wake- and sleep-promoting circuits is associated with narcolepsy, REM sleep behavior disorder, and age-related sleep disturbances.Research has made significant headway in identifying the brain circuits that control wakefulness, non-REM, and REM sleep and has led to a deeper understanding of common sleep disorders and disturbances.

Animals, including humans, require a highly coordinated and flexible system of social behavior and threat evaluation. However, trauma can disrupt this system, with the amygdala implicated as a mediator of these impairments in behavior. Recent evidence has further highlighted the context of infant trauma as a critical variable in determining its immediate and enduring consequences, with trauma experienced from an attachment figure, such as occurs in cases of caregiver-child maltreatment, as particularly detrimental. This review focuses on the unique role of caregiver presence during early-life trauma in programming deficits in social behavior and threat processing. Using data primarily from rodent models, we describe the interaction between trauma and attachment during a sensitive period in early life, which highlights the role of the caregiver’s presence in engagement of attachment brain circuitry and suppressing threat processing by the amygdala. These data suggest that trauma experienced directly from an abusive caregiver and trauma experienced in the presence of caregiver cues produce similar neurobehavioral deficits, which are unique from those resulting from trauma alone. We go on to integrate this information into social experience throughout the lifespan, including consequences for complex scenarios, such as dominance hierarchy formation and maintenance. Keywords: Development, Threat, Amygdala, Social behavior, Dominance hierarchy

Although earlier models of brain circuitry controlling wake-sleep focused on monaminergic and cholinergic arousal systems, recent evidence indicates that these play mainly a modulatory role, and that the backbone of the wake-sleep regulatory system depends upon fast neurotransmitters, such as glutmate and GABA. We review here recent advances in understanding the role these systems play in controlling sleep and wakefulness.

Nucleus accumbens (NAc) is a key region in the brain that is integral to both the reward and the emotional systems. The aim of the current paper is to synthesize the basic and the clinical neuroscience discoveries relevant to the NAc for the purpose of two-way translation. Selected literature on the structure and the functionality of the NAc is reviewed across animal and human studies. Dopamine, gamma-aminobutyric acid (GABA) and glutamate are the three key neurotransmitters that modulate the reward function and the motor activity. Dissociative roles of the core and the shell of the NAc include getting to the reward and staying on task with discretion, respectively. NAc shows decreased activation to reward in the individuals with major depressive disorder and the bipolar disorder, relative to that healthy controls (HC). The “difficult to please” or insatiability in response to reward in the emotional disorders may possibly be explained by such a neural pattern. Furthermore, it is likely that the increased amygdala activity reported in mood disorders could be accentuating the “wanting” of the reward by the virtue of its connections with the NAc, explaining the potential “hot mess”. In contrast, the NAc shows increased reward response in substance use disorders, relative to HC, in response to reward and emotional tasks. Accurate characterization of the NAc and its functionality in the human imaging studies of mood and substance use has important treatment implications.

Real behaviors are binding consequential commitments to a course of action, such as harming another person, buying an Apple watch, or fleeing from danger. Cognitive scientists are generally interested in the psychological and neural processes that cause such real behavior. However, for practical reasons, many scientific studies measure behavior using only hypothetical or imagined stimuli. Generalizing from such studies to real behavior implicitly assumes that the processes underlying the two types of behavior are similar. We review evidence of similarity and differences in hypothetical and real mental processes. In many cases, hypothetical choice tasks give an incomplete picture of brain circuitry that is active during real choice.

Perception of light not only results in image vision, but also modulates a number of biological functions that do not involve image formation, such as pupil light reflex and photoentrainment of circadian rhythm. Such non-image-forming vision is primarily mediated by a subset of retinal ganglion cells, termed as intrinsically photosensitive retinal ganglion cells (ipRGCs), which express the photopigment melanopsin thereby exhibiting intrinsic photosensitivity. Since the groundbreaking discovery of ipRGCs approximately two decades ago, ample evidence suggests that ipRGCs project to various subcortical nuclei, and probably participate in a wider range of physiological processes than initially known. This article reviews important laboratory and clinical evidence and recent progress regarding phototransduction of ipRGCs and brain circuitry in non-image vision.

Background : Trauma has neurobehavioral effects when experienced at any stage of development, but trauma experienced in early life has unique neurobehavioral outcomes related to later life psychiatric sequelae. Recent evidence has further highlighted the context of infant trauma as a critical variable in determining its immediate and enduring consequences. Trauma experienced from an attachment figure, such as occurs in cases of caregiver child maltreatment, is particularly detrimental. Methods : Using data primarily from rodent models, we review the literature on the interaction between trauma and attachment in early life, which highlights the role of the caregiver’s presence in engagement of attachment brain circuitry and suppressing threat processing by the amygdala. We then consider how trauma with and without the caregiver produces long-term changes in emotionality and behavior, and suggest that these experiences initiate distinct pathways to pathology. Results : Together these data suggest that infant trauma processing and its enduring effects are impacted by both the immaturity of brain areas for processing trauma and the unique functioning of the early-life brain, which is biased toward processing information within the attachment circuitry. Conclusion : An understanding of developmental differences in trauma processing as well as the critical role of the caregiver in further altering early life brain processing of trauma is important for developing age-relevant treatment and interventions. Keywords: Trauma; attachment; amygdala; development; stress; sensitive period; infant; maternal care (Published: 8 November 2016) Responsible Editors: Bernet Elzinga, Leiden University, The Netherlands; Christian Schmahl, Central Institute of Mental Health, Germany. This paper is part of the Special Issue: Back to Basics: Integrating Clinical and Scientific Knowledge to Advance the Field of Trauma—Highlights of the ISTSS-2015. More papers from this issue can be found at www.ejpt.net For the abstract or full text in other languages, please see Supplementary files in the column to the right (under ‘Article Tools’). Citation: European Journal of Psychotraumatology 2016, 7 : 31276 - http://dx.doi.org/10.3402/ejpt.v7.31276

Fatigue is one of the most debilitating symptoms in patients with multiple sclerosis (MS). Despite its clinical significance, the aetiology and pathophysiology of MS-related fatigue are not well understood. Current evidence and understanding of the neuroanatomical underpinnings of MS-related fatigue are reviewed in this article. The aims of this paper are to (1) review the findings of previous structural neuroimaging studies on MS-related fatigue and summarize consistent findings regarding brain circuitry associated with fatigue in MS, (2) contextualize these findings with the neurochemistry of the relevant circuits and (3) discuss future perspectives with regard to impact on fatigue management of MS patients and methodological challenges towards improved understanding of fatigue pathogenesis. The detailed understanding of the neuroanatomical underpinnings of fatigue might contribute to the identification of novel treatment targets and factors determining treatment resistance to drugs used in current clinical practice.

The capability of the mammalian brain to generate new neurons through the lifespan has gained much attention for the promise of new therapeutic possibilities especially for the aging brain. One of the brain regions that maintains a neurogenesis‐permissive environment is the dentate gyrus of the hippocampus. Here, new neurons are generated from a pool of multipotent neural progenitor cells to become fully functional neurons that are integrated into the brain circuitry. A growing body of evidence points to the fact that neurogenesis in the adult hippocampus is necessary for certain memory processes, and in mood regulation, while alterations in hippocampal neurogenesis have been associated with a myriad of neurological and psychiatric disorders. More recently, evidence has come to light that new neurons may differ in their vulnerability to environmental and disease‐related influences depending on the time during the life course at which they are exposed. Thus, it has been the topic of intense research in recent years. In this review, we will discuss the complex process and associated functional relevance of hippocampal neurogenesis during the embryonic/postnatal period and in adulthood. We consider the implications of hippocampal neurogenesis during the developmentally critical periods of adolescence and older age. We will further consider the literature surrounding hippocampal neurogenesis and its functional role during these critical periods with a view to providing insight into the potential of harnessing neurogenesis for health and therapeutic benefit.

The advent of the noninvasive brain stimulation (NIBS) technique has paved the way for neural circuit-based treatments for addiction. Recently, evidence from both preclinical and clinical studies has evaluated the use of transcranial magnetic stimulation (TMS) as a safe and cost-effective therapeutic tool for substance use disorders (SUDs). Indeed, repetitive TMS impacts on neural activity inducing short- and long-term effects involving neuroplasticity mechanisms locally within the target area of stimulation and the network level throughout the brain. Here, we provide an integrated view of evidence highlighting the mechanisms of TMS-induced effects on modulating the maladaptive brain circuitry of addiction. We then review the preclinical and clinical findings suggesting rTMS as an effective interventional tool for the treatment of SUDs.

Complex motor skills take considerable time and practice to learn. Without continued practice the level of skill performance quickly degrades, posing a problem for the timely utilization of skilled motor behaviors. Here we quantified the recurring development of vocal motor skills and the accompanying changes in synaptic connectivity in the brain of a songbird, while manipulating skill performance by consecutively administrating and withdrawing testosterone. We demonstrate that a songbird with prior singing experience can significantly accelerate the re-acquisition of vocal performance. We further demonstrate that an increase in vocal performance is accompanied by a pronounced synaptic pruning in the forebrain vocal motor area HVC, a reduction that is not reversed when birds stop singing. These results provide evidence that lasting synaptic changes in the motor circuitry are associated with the savings of motor skills, enabling a rapid recovery of motor performance under environmental time constraints., eLife digest Developing a complex skill, for example learning how to play the violin, takes considerable time and effort. If you then abandon the violin for months or years, your ability to play will deteriorate over time. However, when you do pick up the violin again you will be able to recover your proficiency much faster than you did when learning for the first time. It therefore seems that while first learning a complex motor skill, some sort of memory is formed and stored. Learning and memory in general rely on the patterns of connections, called synapses, among neurons in the brain. Early in development, neurons make too many of these connections. This network is then refined over time as unneeded connections are discarded. However, the structural changes to the network that make it easier to re-acquire a skill were not well understood. Canaries are a useful example of this sort of learning. Young males learn complex songs that are critical for their ability to attract a mate, and can quickly re-acquire their songs at the beginning of each mating season. Female canaries do not normally sing but will develop songs if they are implanted with a testosterone-releasing device. When the implant is removed, they stop singing. To investigate how songbirds re-acquire songs, Vellema et al. gave female canaries a testosterone implant, and the birds gradually developed songs. The implant was then removed, and for two and a half months the birds did not sing. Vellema et al. then gave the canaries a second testosterone treatment. The canaries rapidly began to sing songs that were strikingly similar to the ones they sang during the initial learning period. Examining the brains of these canaries revealed that major structural changes in brain connections occurred while the canaries first developed their songs. After the initial period of testosterone exposure, the female canaries had fewer synapses in a brain region that is associated with learning and producing motor tasks. Importantly, this reorganization of the brain circuitry was irreversible. These findings provide fundamental insights into how we learn and maintain new motor skills. Similar rapid re-learning phenomena are observed in other areas of neuroscience, and future research can explore whether the mechanism described here extends to these areas. Possibly, this mechanism could also illuminate how we can regain skills lost after trauma or injury.

Deep brain stimulation (DBS) has been used in clinical settings for many years despite a paucity of knowledge related to the anatomical and functional substrates that lead to benefits and/or side-effects in various disease contexts. In order to maximize the potential of this approach in humans, a better understanding of its mechanisms of action is absolutely necessary. However, the existing micro-stimulators available for pre-clinical models, are limited by the lack of relevant small size devices. This absence prevents sustained chronic stimulation and real time monitoring of animals during stimulation, parameters that are critical for comparison to clinical findings. We therefore sought to develop and refine a novel small wireless micro-stimulator as a means by which to study consequent behavioural to molecular changes in experimental animals. Building on previous work from our group, we refined our implantable micro-stimulator prototype, to be easily combined with intravital 2-photon imaging. Using our prototype we were able to replicate the well described clinical benefits on motor impairment in a mouse model of Parkinson’s disease in addition to capturing microglia dynamics live during stimulation. We believe this new device represents a useful tool for performing pre-clinical studies as well as dissecting brain circuitry and function.

Aging is associated with an increased ability to delay gratification. Moreover, even when matched for performance, young and aged subjects recruit distinct brain circuitry to complete complex cognitive tasks. Experiments herein used an optogenetic approach to test whether altered recruitment of the basolateral amygdala (BLA), a brain region implicated in valuation of reward-cost contingencies, contributes to age-dependent changes in intertemporal decision making. BLA inactivation while rats deliberated prior to choices between options that yielded either small, immediate or large, delayed rewards rendered both young and aged rats less impulsive. In contrast, BLA inactivation after choices were made (during evaluation of choice outcomes) rendered young rats more impulsive but had no effect in aged rats. These data define multiple, temporally-discrete roles for BLA circuits in intertemporal decision making and implicate altered recruitment of BLA in the elevated preference for delayed rewards that is characteristic of advanced age.Impact StatementBasolateral amygdala (BLA) performs multiple, temporally-discrete functions during intertemporal decision making. Differential engagement of BLA contributes to the enhanced ability to delay gratification that is characteristic of advanced ages.

Opioid addiction has reached the epidemic status in the United States in recent years. A multitude of factors have contributed to an alarming increase in misuse and health issues related to these drugs. Although medications exist to treat some aspects of opioid addiction since long ago, relapse and fatality rates remain very high despite their long-term availability. Therefore, more research devoted to better understanding its neural substrates is needed to aid developing new treatment options. Interestingly, a number of studies show the cerebellum to be involved in the effects of opioids and addiction-related processes, though it is not usually regarded as part of the opioid addiction-related brain circuitry. This review provides a summary of cerebellar anatomy and synaptic organization, followed by discussing the studies reporting cerebellar involvement in opioid effects in animals and humans, and their possible role in opioid addiction. Additionally, future experimental approaches will be proposed. We hope this work will contribute considering the cerebellum as an integral part of the circuitry underlying opioid-related disorders.

It is commonly accepted that brain plasticity occurs in wakefulness and sleep. However, how these different brain states work in concert to create long-lasting changes in brain circuitry is unclear. Considering that wakefulness and sleep are profoundly different brain states on multiple levels (e.g., cellular, molecular and network activation), it is unlikely that they operate exactly the same way. Rather it is probable that they engage different, but coordinated, mechanisms. In this article we discuss how plasticity may be divided across the sleep–wake cycle, and how synaptic changes in each brain state are linked. Our working model proposes that waking experience triggers short-lived synaptic events that are necessary for transient plastic changes and mark (i.e., ‘prime’) circuits and synapses for further processing in sleep. During sleep, synaptic protein synthesis at primed synapses leads to structural changes necessary for long-term information storage.

Obsessive compulsive disorder (OCD) is a common, disabling psychiatric disease characterized by persistent, intrusive thoughts and ritualistic, repetitive behaviors. Deep brain stimulation (DBS) is thought to alleviate OCD symptoms by modulating underlying disturbances in normal cortico-striato-thalamo-cortical (CSTC) circuitry. Stimulation of the ventral portion of the anterior limb of the internal capsule (ALIC) and underlying ventral striatum (“ventral capsule/ventral striatum” or “VC/VS” target) received U.S. FDA approval in 2009 for patients with severe, treatment-refractory OCD. Over the decades, DBS surgical outcome studies have led to an evolution in the electrical stimulation target. In parallel, advancements in neuroimaging techniques have allowed investigators to better visualize and define CSTC circuits underlying the pathophysiology of OCD. A critical analysis of these new data suggests that the therapeutic mechanism of DBS for OCD likely involves neuromodulation of a widespread cortical/subcortical network, accessible by targeting fiber bundles in the ventral ALIC that connect broad network regions. Future studies will include advances in structural and functional imaging, analysis of physiological recordings, and utilization of next-generation DBS devices. These tools will enable patient-specific optimization of DBS therapy, which will hopefully further improve outcomes.

Gambling disorder (GD) has important similarities with substance use disorders (SUDs) in terms of both diagnostic criteria and underlying mechanisms of action. With regard to diagnostic criteria, only craving is not present as a formal criterion in DSM-5 GD, and chasing losses is not present in SUDs. All other major diagnostic criteria such as loss of control over gambling, tolerance, withdrawal, and negative consequences due to gambling overlap with those of SUD. With regard to underlying mechanisms and vulnerability factors, higher impulsivity, abnormalities in decision-making, deficient executive functions, and related fronto-striatal brain circuitry abnormalities are related to the development and course of both SUD and GD. However, there are also differences between GD and SUD. In gambling, cognitive factors such as risk-taking and decision-making are intrinsically related to the addictive behavior itself, whereas in SUD these effects can also be associated with the pharmacological effect or the neurotoxicity related to (chronic) substance use. Moreover misperceptions with regard to gambling, the experience and interpretation of near misses, and the processing of (potential) rewards and losses influence the experience of gambling, which is not true for SUD. Importantly, these aspects also differ between disordered gamblers and non-problematic gamblers and are thus unique for GD and consitute a risk for relapse. Both shared and unique mechanisms are relevant as targets for the treatment of GD. This chapter concludes with a discussion on novel treatment methods that target some of the working mechanisms shared by GD and SUDs.

Substance abuse disorder is a chronically relapsing disease that is characterized in part by compulsion to seek and take drug in the presence of adverse consequences and in inappropriate situations. Compulsivity develops progressively, and is hypothesized to derive from dysfunction in motivational and reward processing. Preclinical models have been developed that recapitulate endophenotypes of compulsive drug behaviors to study the pathophysiology and etiology of compulsivity. These models have been used to identify adaptations in brain circuitry, neurotransmission, and epigenetics that underlie compulsive drug use, and have provided a framework for theories that describe the development and expression of compulsivity.

Sex differences in mental rotation, robust in adults, have recently been reported for infants’ looking times although the pattern of results is not completely conclusive. In this context, organizational effects of gonadal steroids affecting the neural circuitry underlying spatial cognition could be (partly) responsible for the early sex difference. In the present study testosterone and estradiol levels measured in amniotic fluid via ultra performance liquid chromatography and tandem mass spectrometry were used to examine the role of prenatal sex hormones on infants’ looking times during mental rotation. N = 208 six-month-old infants participated in an expectation of violation task with 3D cube figures. Mental rotation was defined as the difference in looking times for familiar versus mirrored cube figures whereas vigilance was defined as the sum of both looking times. Sex differences were absent for mental rotation as well as for vigilance. Most importantly, however, for boys mental rotation but not vigilance was correlated with prenatal testosterone but not with estradiol. For girls mental rotation but not vigilance was correlated with prenatal estradiol but not with testosterone although it has to be noted that the testosterone values for girls suffered from a floor effect. Only 5% of the within-sex variance was due to prenatal sex hormones indicating small effects. These findings extend our knowledge concerning organizational effects of prenatal sex hormones on the brain circuitry underlying spatial cognition.

Opioid analgesics, most of which act through mu opioid receptors, have long represented valuable therapeutic agents to treat severe pain. Concerted drug development efforts for over a 100 years have resulted in a large variety of opioid analgesics used in the clinic, but all of them continue to exhibit the side effects, especially respiratory depression, that have long plagued the use of morphine. The recent explosion in fatalities resulting from overdose of prescription and synthetic opioids has dramatically increased the need for safer analgesics, but recent developments in mu receptor research have provided new strategies to develop such drugs. This chapter reviews recent advances in developing novel opioid analgesics from an understanding of mu receptor structure and function. This includes a summary of the mechanism of agonist binding deduced from the crystal structure of mu receptors. It will also highlight the development of novel agonist mechanisms, including biased agonists, bivalent ligands, and allosteric modulators of mu receptor function, and describe how receptor phosphorylation modulates these pathways. Finally, it will summarize research on the alternative pre-mRNA splicing mechanisms that produces a multiplicity of mu receptor isoforms. Many of these isoforms exhibit different pharmacological specificities and brain circuitry localization, thus providing an opportunity to develop novel drugs with increased therapeutic windows.

In 1962, Joseph Altman described that the brain generates neurons after the postnatal period, and this continues throughout your life (Altman, 1962). This was a breakthrough in the neuroscience field because before this the accepted paradigm was that the brain only generated neurons during the embryonal development. This discovery has been controversial ever since, especially since one of the areas of the brain with neurogenic properties is the hippocampus, which is the area involved in memory storage and neurodegenerative processes. The adult hippocampal neurogenesis modulates in response to different environmental factors. In this article, we review how exercise and cognitive and sexual activity can regulate the generation of new neurons in the hippocampal in an adult brain and the impact of these new neurons in the brain circuitry.

Changes in prefrontal cortex are thought to be responsible for many of the characteristic behavioral changes that are seen during adolescence and late adulthood. Disruption of prefrontal cortex is an early sign for many developmental, neurological, and psychiatric disorders. Goal directed eye movements, such as Anti-saccades, have been shown to have high sensitivity as a gross assessment of prefrontal lobe function. Previous studies on the developmental changes of saccades across age have shown that stimulus-driven and goal-directed eye movements follow a U-shaped trend with peaks in performance occuring during adolescence. Using novel tablet-based pointing tasks, modeled on eye movement tests, this study aims to provide a preliminary understanding of how age affects manual pointing performance, in order to more easily track behavioral changes of the prefrontal cortex. In this study, 82 participants between the ages of 10 and 63 were recruited to participate. Results show that similarly to saccades, manual pointing responses are age dependent with fastest response times found during late adolescence to early adulthood (U-shaped curves). Importantly, we also demonstrated significant differences in the effect of age in stimulus-driven (Pro-point) and goal-directed (Anti-point) pointing tasks. The effect of age on response time (RT) is greater on Anti-point compared to Pro-point task (with a 79 ms greater mean decrease during early development and a 148 ms greater mean increase during later aging). Further, for Pro-point task, the U-shaped curve flattens at about 45 years whereas for Anti-point task the U-shaped curve continues up to the maximum age tested (about 60 years). This dissociation between age-related changes in sensorimotor and cognitive performance suggests independent development of associated brain circuity. Thus, changes of performance in disease that are specific for age and task may be able to help identify brain circuitry involved. Finally, given that these tablet-based pointing tasks show similar age-related patterns reported previously with eye-tracking technology, our findings suggest that such tablet-based tasks may provide an inexpensive, quick, and more practical way of detecting neurological deficits or tracking cognitive changes.

Sex differences in self-control become apparent during preschool years. Girls are better able to delay their gratification and show less attention problems and overactive behavior than boys. In this context, organizational effects of gonadal steroids affecting the neural circuitry underlying self-control could be responsible for these early sex differences. In the present study testosterone levels measured in amniotic fluid (via ultra performance liquid chromatography and tandem mass spectrometry) were used to examine the role of organizational sex hormones on self-control. One hundred and twenty-two 40-month-old children participated in a delay of gratification task (DoG task) and their parents reported on their attention problems and overactive behavior. Girls waited significantly longer for their preferred reward than boys, and significantly more girls than boys waited the maximum period of time, providing evidence for sex differences in delay of gratification. Boys that were rated as suffering from more attention problems and overactive behavior waited significantly shorter in the DoG task. Amniotic testosterone measures were reliable in boys only. Most importantly, boys who waited shorter in the DoG task and boys who were reported to suffer from more attention problems and overactive behavior had higher prenatal testosterone levels. These findings extend our knowledge concerning organizational effects of testosterone on the brain circuitry underlying self-control in boys, and are of relevance for understanding how sex differences in behavioral disorders are connected with a lack of self-control.

Knowledge of brain circuitry is critical for understanding the organization, function, and evolution of central nervous systems. Most commonly, brain connections have been elucidated using histological and experimental methods that require animal sacrifice. On the other hand, magnetic resonance diffusion tensor imaging and associated tractography have emerged as a preferred method to noninvasively visualize brain white matter tracts. However, existing studies have primarily examined large, heavily myelinated fiber tracts. Whether tractography can visualize fiber bundles that contain thin and poorly myelinated axons is uncertain. To address this question, the midbrain auditory pathway to the thalamus was investigated in Alligator. This species was chosen because of its evolutionary importance as it is the reptilian group most closely related to birds and because its brain contains many thin and poorly myelinated tracts. Furthermore, this auditory pathway is well documented in other reptiles, including a related crocodilian. Histological observations and experimental determination of anterograde connections confirmed this path in Alligator. Tractography identified these tracts in Alligator and provided a 3-dimensional picture that accurately identified the neural elements of this circuit. In addition, tractography identified one possible unrecognized pathway. These results demonstrate that tractography can visualize circuits containing thin, poorly myelinated fibers. These findings open the door for future studies to examine these types of pathways in other vertebrates.

Parenting recruits a distributed network of brain structures (and neuromodulators) that coordinates caregiving responses attuned to the young's affect, needs, and developmental stage. Many of these structures and connections undergo significant structural and functional plasticity, mediated by the interplay between maternal hormones and social experience while the reciprocal relationship between the mother and her infant forms and develops. These alterations account for the remarkable behavioral plasticity of mothers. This review will examine the molecular and neurobiological modulation and plasticity through which parenting develops and adjusts in new mothers, primarily discussing recent findings in nonhuman animals. A better understanding of how parenting impacts the brain at the molecular, cellular, systems/network, and behavioral levels is likely to significantly contribute to novel strategies for treating postpartum neuropsychiatric disorders in new mothers, and critical for both the mother's physiological and mental health and the development and well-being of her young.