Early life adversity reduces affiliative behavior with a stressed cagemate and leads to sex-specific alterations in corticosterone responses in adult mice.

Experiencing early life adversity (ELA) alters stress physiology and increases the risk for developing psychiatric disorders. The social environment can influence dynamics of stress responding and buffer and/or transfer stress across individuals. Yet, the impact of ELA on sensitivity to the stress of others and social behavior following stress is unknown. Here, to test the impact of ELA on social and physiological responses to stress, circulating blood corticosterone (CORT) and social behaviors were assessed in adult male and female mice reared under limited bedding and nesting (LBN) or control conditions. To induce stress, one cagemate of a pair-housed cage underwent a footshock paradigm and was then returned to their unshocked partner. CORT was measured in both groups of mice 20 or 90 min after stress exposure, and social behaviors were recorded and analyzed. ELA rearing influenced the CORT response to stress in a sex-specific manner. In males, both control and ELA-reared mice exhibited similar stress transfer to unshocked cagemates and similar CORT dynamics. In contrast, ELA females showed a heightened stress transfer to unshocked cagemates, and sustained elevation of CORT relative to controls, indicating enhanced stress contagion and a failure to terminate the stress response. Behaviorally, ELA females displayed decreased allogrooming and increased investigative behaviors, while ELA males showed reduced huddling. Together, these findings demonstrate that ELA influenced HPA axis dynamics, social stress contagion and social behavior. Further research is needed to unravel the underlying mechanisms and long-term consequences of ELA on stress systems and their impact on behavioral outcomes.

Central amygdala CRF+ neurons promote heightened threat reactivity following early life adversity in mice.

Failure to appropriately predict and titrate reactivity to threat is a core feature of fear and anxiety-related disorders and is common following early life adversity (ELA). A population of neurons in the lateral central amygdala (CeAL) expressing corticotropin releasing factor (CRF) have been proposed to be key in processing threat of different intensities to mediate active fear expression. Here, we use in vivo fiber photometry to show that ELA results in sex-specific changes in the activity of CeAL CRF+ neurons, yielding divergent mechanisms underlying the augmented startle in ELA mice, a translationally relevant behavior indicative of heightened threat reactivity and hypervigilance. Further, chemogenic inhibition of CeAL CRF+ neurons selectively diminishes startle and produces a long-lasting suppression of threat reactivity. These findings identify a mechanism for sex-differences in susceptibility for anxiety following ELA and have broad implications for understanding the neural circuitry that encodes and gates the behavioral expression of fear.

Early life adversity reduces affiliative behavior towards a distressed cagemate and leads to sex-specific alterations in corticosterone responses.

Experiencing early life adversity (ELA) alters stress physiology and increases the risk for developing psychiatric disorders. The social environment can influence dynamics of stress responding and buffer and/or transfer stress across individuals. Yet, the impact of ELA on sensitivity to the stress of others and social behavior following stress is unknown. Here, to test the impact of ELA on social and physiological responses to stress, circulating blood corticosterone (CORT) and social behaviors were assessed in adult male and female mice reared under limited bedding and nesting (LBN) or control conditions. To induce stress, one cagemate of a pair-housed cage underwent a footshock paradigm and was then returned to their unshocked partner. CORT was measured in both mice 20 or 90 minutes after stress exposure, and social behaviors were recorded and analyzed. ELA rearing influenced the CORT response to stress in a sex-specific manner. In males, both control and ELA-reared mice exhibited similar stress transfer to unshocked cagemates and similar CORT dynamics. In contrast, ELA females showed a heightened stress transfer to unshocked cagemates, and sustained elevation of CORT relative to controls, indicating enhanced stress contagion and a failure to terminate the stress response. Behaviorally, ELA females displayed decreased allogrooming and increased investigative behaviors, while ELA males showed reduced huddling. Together, these findings demonstrate that ELA influenced HPA axis dynamics, social stress contagion and social behavior. Further research is needed to unravel the underlying mechanisms and long-term consequences of ELA on stress systems and their impact on behavioral outcomes.

Levetiracetam Increases Hippocampal Blood Flow in Alzheimer's Disease as Measured by Arterial Spin Labelling MRI.

BACKGROUND: Patients with Alzheimer's disease (AD) have an increased risk of developing epileptiform discharges, which is associated with a more rapid rate of progression. This suggests that suppression of epileptiform activity could have clinical benefit in patients with AD. OBJECTIVE: In the current study, we tested whether acute, intravenous administration of levetiracetam led to changes in brain perfusion as measured with arterial spin labeling MRI (ASL-MRI) in AD. METHODS: We conducted a double-blind, within-subject crossover design study in which participants with mild AD (n = 9) received placebo, 2.5 mg/kg, and 7.5 mg/kg of LEV intravenously in a random order in three sessions. Afterwards, the participants underwent ASL-MRI. RESULTS: Analysis of relative cerebral blood flow (rCBF) between 2.5 mg of levetiracetam and placebo showed significant decreases in a cluster that included the posterior cingulate cortex, the precuneus, and the posterior part of the cingulate gyrus, while increased cerebral blood flow was found in both temporal lobes involving the hippocampus. CONCLUSION: Administration of 2.5 mg/kg of LEV in patients without any history of epilepsy leads to changes in rCBF in areas known to be affected in the early stages of AD. These areas may be the focus of the epileptiform activity. Larger studies are needed to confirm the current findings.

Neural activation associated with outgroup helping in adolescent rats.

Prosocial behavior, helping others in need in particular, occurs preferentially in response to the perceived distress of one's own group members or ingroup. To investigate the development of ingroup bias, neural activity during a helping test was analyzed in adolescent and adult rats. Although adults selectively released trapped ingroup members, adolescent rats helped both ingroup and outgroup members, suggesting that ingroup bias emerges in adulthood. Analysis of brain-wide neural activity, indexed by expression of the early-immediate gene c-Fos, revealed increased activity for ingroup members across a broad set of regions previously associated with empathy. Adolescents showed reduced hippocampal and insular activity and increased orbitofrontal cortex activity compared to adults. Non-helper adolescents demonstrated increased amygdala connectivity. These findings demonstrate that biases for group-dependent prosocial behavior develop with age in rats and suggest that specific brain regions contribute to prosocial selectivity, pointing to possible targets for the functional modulation of ingroup bias.

Hormonal Regulation of Oligodendrogenesis I: Effects across the Lifespan.

The brain's capacity to respond to changing environments via hormonal signaling is critical to fine-tuned function. An emerging body of literature highlights a role for myelin plasticity as a prominent type of experience-dependent plasticity in the adult brain. Myelin plasticity is driven by oligodendrocytes (OLs) and their precursor cells (OPCs). OPC differentiation regulates the trajectory of myelin production throughout development, and importantly, OPCs maintain the ability to proliferate and generate new OLs throughout adulthood. The process of oligodendrogenesis, the creation of new OLs, can be dramatically influenced during early development and in adulthood by internal and environmental conditions such as hormones. Here, we review the current literature describing hormonal regulation of oligodendrogenesis within physiological conditions, focusing on several classes of hormones: steroid, peptide, and thyroid hormones. We discuss hormonal regulation at each stage of oligodendrogenesis and describe mechanisms of action, where known. Overall, the majority of hormones enhance oligodendrogenesis, increasing OPC differentiation and inducing maturation and myelin production in OLs. The mechanisms underlying these processes vary for each hormone but may ultimately converge upon common signaling pathways, mediated by specific receptors expressed across the OL lineage. However, not all of the mechanisms have been fully elucidated, and here, we note the remaining gaps in the literature, including the complex interactions between hormonal systems and with the immune system. In the companion manuscript in this issue, we discuss the implications of hormonal regulation of oligodendrogenesis for neurological and psychiatric disorders characterized by white matter loss. Ultimately, a better understanding of the fundamental mechanisms of hormonal regulation of oligodendrogenesis across the entire lifespan, especially in vivo, will progress both basic and translational research.

Hormonal Regulation of Oligodendrogenesis II: Implications for Myelin Repair.

Alterations in myelin, the protective and insulating sheath surrounding axons, affect brain function, as is evident in demyelinating diseases where the loss of myelin leads to cognitive and motor dysfunction. Recent evidence suggests that changes in myelination, including both hyper- and hypo-myelination, may also play a role in numerous neurological and psychiatric diseases. Protecting myelin and promoting remyelination is thus crucial for a wide range of disorders. Oligodendrocytes (OLs) are the cells that generate myelin, and oligodendrogenesis, the creation of new OLs, continues throughout life and is necessary for myelin plasticity and remyelination. Understanding the regulation of oligodendrogenesis and myelin plasticity within disease contexts is, therefore, critical for the development of novel therapeutic targets. In our companion manuscript, we review literature demonstrating that multiple hormone classes are involved in the regulation of oligodendrogenesis under physiological conditions. The majority of hormones enhance oligodendrogenesis, increasing oligodendrocyte precursor cell differentiation and inducing maturation and myelin production in OLs. Thus, hormonal treatments present a promising route to promote remyelination. Here, we review the literature on hormonal regulation of oligodendrogenesis within the context of disorders. We focus on steroid hormones, including glucocorticoids and sex hormones, peptide hormones such as insulin-like growth factor 1, and thyroid hormones. For each hormone, we describe whether they aid in OL survival, differentiation, or remyelination, and we discuss their mechanisms of action, if known. Several of these hormones have yielded promising results in both animal models and in human conditions; however, a better understanding of hormonal effects, interactions, and their mechanisms will ultimately lead to more targeted therapeutics for myelin repair.

Juvenile exposure to acute traumatic stress leads to long-lasting alterations in grey matter myelination in adult female but not male rats.

Stress early in life can have a major impact on brain development, and there is increasing evidence that childhood stress confers vulnerability for later developing psychiatric disorders. In particular, during peri-adolescence, brain regions crucial for emotional regulation, such as the prefrontal cortex (PFC), amygdala (AMY) and hippocampus (HPC), are still developing and are highly sensitive to stress. Changes in myelin levels have been implicated in mental illnesses and stress effects on myelin and oligodendrocytes (OLs) are beginning to be explored as a novel and underappreciated mechanism underlying psychopathologies. Yet there is little research on the effects of acute stress on myelin during peri-adolescence, and even less work exploring sex-differences. Here, we used a rodent model to test the hypothesis that exposure to acute traumatic stress as a juvenile would induce changes in OLs and myelin content across limbic brain regions. Male and female juvenile rats underwent 3 h of restraint stress with exposure to a predator odor on postnatal day (p) 28. Acute stress induced a physiological response, increasing corticosterone release and reducing weight gain in stress-exposed animals. Brain sections containing the PFC, AMY and HPC were taken either in adolescence (p40), or in adulthood (p95) and stained for markers of OLs and myelin. We found that acute stress induced sex-specific changes in grey matter (GM) myelination and OLs in both the short- and long-term. Exposure to a single stressor as a juvenile increased GM myelin content in the AMY and HPC in p40 males, compared to the respective control group. At p40, corticosterone release during stress exposure was also positively correlated with GM myelin content in the AMY of male rats. Single exposure to juvenile stress also led to long-term effects exclusively in female rats. Compared to controls, stress-exposed females showed reduced GM myelin content in all three brain regions. Acute stress exposure decreased PFC and HPC OL density in p40 females, perhaps contributing towards this observed long-term decrease in myelin content. Overall, our findings suggest that the juvenile brain is vulnerable to exposure to a brief severe stressor. Exposure to a single short traumatic event during peri-adolescence produces long-lasting changes in GM myelin content in the adult brain of female, but not male, rats. These findings highlight myelin plasticity as a potential contributor to sex-specific sensitivity to perturbation during a critical window of development.

Neural correlates of ingroup bias for prosociality in rats.

Prosocial behavior, in particular helping others in need, occurs preferentially in response to distress of one's own group members. In order to explore the neural mechanisms promoting mammalian helping behavior, a discovery-based approach was used here to identify brain-wide activity correlated with helping behavior in rats. Demonstrating social selectivity, rats helped others of their strain ('ingroup'), but not rats of an unfamiliar strain ('outgroup'), by releasing them from a restrainer. Analysis of brain-wide neural activity via quantification of the early-immediate gene c-Fos identified a shared network, including frontal and insular cortices, that was active in the helping test irrespective of group membership. In contrast, the striatum was selectively active for ingroup members, and activity in the nucleus accumbens, a central network hub, correlated with helping. In vivo calcium imaging showed accumbens activity when rats approached a trapped ingroup member, and retrograde tracing identified a subpopulation of accumbens-projecting cells that was correlated with helping. These findings demonstrate that motivation and reward networks are associated with helping an ingroup member and provide the first description of neural correlates of ingroup bias in rodents.

Regional gray matter oligodendrocyte- and myelin-related measures are associated with differential susceptibility to stress-induced behavior in rats and humans.

Individual reactions to traumatic stress vary dramatically, yet the biological basis of this variation remains poorly understood. Recent studies demonstrate the surprising plasticity of oligodendrocytes and myelin with stress and experience, providing a potential mechanism by which trauma induces aberrant structural and functional changes in the adult brain. In this study, we utilized a translational approach to test the hypothesis that gray matter oligodendrocytes contribute to traumatic-stress-induced behavioral variation in both rats and humans. We exposed adult, male rats to a single, severe stressor and used a multimodal approach to characterize avoidance, startle, and fear-learning behavior, as well as oligodendrocyte and myelin basic protein (MBP) content in multiple brain areas. We found that oligodendrocyte cell density and MBP were correlated with behavioral outcomes in a region-specific manner. Specifically, stress-induced avoidance positively correlated with hippocampal dentate gyrus oligodendrocytes and MBP. Viral overexpression of the oligodendrogenic factor Olig1 in the dentate gyrus was sufficient to induce an anxiety-like behavioral phenotype. In contrast, contextual fear learning positively correlated with MBP in the amygdala and spatial-processing regions of the hippocampus. In a group of trauma-exposed US veterans, T1-/T2-weighted magnetic resonance imaging estimates of hippocampal and amygdala myelin associated with symptom profiles in a region-specific manner that mirrored the findings in rats. These results demonstrate a species-independent relationship between region-specific, gray matter oligodendrocytes and differential behavioral phenotypes following traumatic stress exposure. This study suggests a novel mechanism for brain plasticity that underlies individual variance in sensitivity to traumatic stress.

Relative contributions and mapping of ventral tegmental area dopamine and GABA neurons by projection target in the rat.

The ventral tegmental area (VTA) is a heterogeneous midbrain structure that contains dopamine (DA), GABA, and glutamate neurons that project to many different brain regions. Here, we combined retrograde tracing with immunocytochemistry against tyrosine hydroxylase (TH) or glutamate decarboxylase (GAD) to systematically compare the proportion of dopaminergic and GABAergic VTA projections to 10 target nuclei: anterior cingulate, prelimbic, and infralimbic cortex; nucleus accumbens core, medial shell, and lateral shell; anterior and posterior basolateral amygdala; ventral pallidum; and periaqueductal gray. Overall, the non-dopaminergic component predominated VTA efferents, accounting for more than 50% of all projecting neurons to each region except the nucleus accumbens core. In addition, GABA neurons contributed no more than 20% to each projection, with the exception of the projection to the ventrolateral periaqueductal gray, where the GABAergic contribution approached 50%. Therefore, there is likely a significant glutamatergic component to many of the VTA's projections. We also found that VTA cell bodies retrogradely labeled from the various target brain regions had distinct distribution patterns within the VTA, including in the locations of DA and GABA neurons. Despite this patterned organization, VTA neurons comprising these different projections were intermingled and never limited to any one subregion. These anatomical results are consistent with the idea that VTA neurons participate in multiple distinct, parallel circuits that differentially contribute to motivation and reward. While attention has largely focused on VTA DA neurons, a better understanding of VTA subpopulations, especially the contribution of non-DA neurons to projections, will be critical for future work.

Dual enhancement mechanisms for overnight motor memory consolidation.

Our brains are constantly processing past events [1]. These off-line processes consolidate memories, leading in the case of motor skill memories to an enhancement in performance between training sessions. A similar magnitude of enhancement develops over a night of sleep following an implicit task, when a sequence of movements is acquired unintentionally, or following an explicit task, when the same sequence is acquired intentionally [2]. What remains poorly understood, however, is whether these similar offline improvements are supported by similar circuits, or through distinct circuits. We set out to distinguish between these possibilities by applying Transcranial Magnetic Stimulation (TMS), over the primary motor cortex (M1) or the inferior parietal lobule (IPL) immediately after learning in either the explicit or implicit task. These brain areas have both been implicated in encoding aspects of a motor sequence, and subsequently supporting offline improvements over sleep [3-5]. Here we show that offline improvements following the explicit task are dependent upon a circuit that includes M1 but not IPL. By contrast, offline improvements following the implicit task are dependent upon a circuit that includes IPL but not M1. Our work establishes the critical contribution made by M1 and IPL circuits to offline memory processing, and reveals that distinct circuits support similar offline improvements.

Flipping the switch: mechanisms that regulate memory consolidation.

Memories can follow different processing routes. For example, some memories are enhanced during wakefulness while the enhancement of others is delayed until sleep. Converging evidence suggests that inhibitory mechanisms can 'switch off' a processing route, thereby preventing the consolidation of select memories during wakefulness. This switch arises due to an actively imposed 'bottleneck' generated by the brain. Transcranial magnetic stimulation (TMS) can interfere with this bottleneck, allowing multiple memories to be consolidated simultaneously during wakefulness. This bottleneck restricts memory processing, perhaps allowing for the selection of only rewarded, or relevant memories. Overall, this bottleneck makes it necessary to select memories for consolidation, and the state of a switch ('on' or 'off') determines whether or not a memory is subsequently consolidated. Understanding how memory consolidation is regulated may provide novel therapeutic strategies.

Memory processing: the critical role of neuronal replay during sleep.

Patterns of neuronal activity present during learning in the hippocampus are replayed during sleep. A new study highlights the functional importance of this neurophysiological phenomenon by showing that neuronal replay is critical for memory processing over a night of sleep.

Cross-talk between CD4+ T-cells and neural stem/progenitor cells.

Immune-neural interactions dictate both lesion formation and repair in multiple sclerosis (MS). MS pathogenesis is mediated by the interplay of invading immune cells, neurons, glia, and endogenous stores of neural stem/progenitor cells (NPCs). However, the signals important in this cross-talk are not well defined. We utilized a co-culture method and flow cytometric analysis capable of detecting outcomes for both cell types. Here we describe the effects of NPCs on three different CD4+ subtypes (Th1, Th2, and Th17) and vice versa. Utilizing lpr (Fas receptor-deficient) and gld (Fas ligand-deficient) NPC lines, we further define the role of Fas in this neuroimmune cross-talk. We show that only the Th1 subtype is capable of inducing NPC cell death, and this is independent of Fas activation. Conversely, NPCs specifically kill pro-inflammatory Th1 and Th17 cells in a contact-dependent manner without affecting Th2 survival. Further investigation into these effects revealed that FasL expressed by NPCs mediates Th17 apoptosis. Additionally NPC/T-cell cross-talk modulates FasL expression in both cell types, while Fas receptor levels remains static. These findings illuminate the direct neuropathogenic effects of T-cells, as well as help define the immunomodulatory capacity of NPCs. We have elucidated novel interactions that may be critical in MS pathogenesis.