The Next 50 Years of Neuroscience.

On the 50th anniversary of the Society for Neuroscience, we reflect on the remarkable progress that the field has made in understanding the nervous system, and look forward to the contributions of the next 50 years. We predict a substantial acceleration of our understanding of the nervous system that will drive the development of new therapeutic strategies to treat diseases over the course of the next five decades. We also see neuroscience at the nexus of many societal topics beyond medicine, including education, consumerism, and the justice system. In combination, advances made by basic, translational, and clinical neuroscience research in the next 50 years have great potential for lasting improvements in human health, the economy, and society.

Exposure to in utero inflammation increases locomotor activity, alters cognitive performance and drives vulnerability to cognitive performance deficits after acute immune activation.

Fetal exposure to intrauterine inflammation (IUI) affects brain development. Using intrauterine lipopolysaccharide (LPS) administration to induce a localized, rather than a systemic, inflammation, we have previously shown that IUI increases cytokine expression and microglia number, and reduces white matter in the brains of exposed offspring. Clinical data suggest that IUI may increase the risk for cognitive and neurodevelopmental disorders, however, IUI is often found in the context of preterm birth, making it difficult to disentangle the adverse effects of inflammation from those related to prematurity. Therefore, using a mouse model of IUI that does not involve preterm birth, operant tasks were used to evaluate motivation, attention, impulsivity, and locomotion. IUI-exposed offspring were found to have increased locomotion and increased motivation (females only), and testing in the 5-choice serial reaction time task (5-CSRTT) showed that IUI-exposed offspring performed more trials and could respond accurately at a shorter stimulus length. We have previously shown that IUI animals have a potentiated cytokine response to a "second hit" (acute LPS injection) in adulthood, so animals' performance in the 5CSRTT was evaluated following an acute injection of LPS. As opposed to the improved performance observed under baseline conditions, IUI exposed animals demonstrated a greater decrease in performance after an acute LPS administration. To identify putative molecular mechanisms underlying this potentiated decline in cognitive performance, PFC samples were collected immediately after post-LPS cognitive testing and targeted gene expression analysis was correlated with specific measures of cognitive performance. Three receptors important for neuron-microglia crosstalk were found to correlate with task performance in the males following acute LPS administration. These data demonstrate that early life exposure to localized inflammation of the uterus, in the absence of prematurity, increases locomotor activity and improves some aspects of cognitive performance, but drives a vulnerability for adult cognitive performance deficits in response to acute infection.

Housing and testing in mixed-sex rooms increases motivation and accuracy during operant testing in both male and female mice.

Operant behavior tasks are widely used in neuroscience research, but little is known about how variables such as housing and testing conditions affect rodent operant performance. We have previously observed differences in operant performance in male and female mice depending on whether mice were housed and tested in rooms containing only one sex versus rooms containing both sexes. Here, male and female mice in either single-sex or mixed sex housing rooms were trained on fixed ratio 1 (FR1) and progressive ratio (PR) tasks. For both sexes, animals in the mixed sex room had more accurate performance in FR1 and were more motivated in the PR task. We then moved the single sex housed animals to the mixed sex room and vice versa. Animals that started in mixed sex housing had no change to PR, but both sexes who started in single sex housing were more motivated after the switch. Additionally, the females that moved into single-sex housing performed less accurately in FR1. We conclude that housing and testing conditions can affect performance on FR1 and PR tasks. As these tasks are commonly used as training steps to more complex tasks, housing and testing conditions should be carefully considered during experiment design and reported in publications.

Intrauterine inflammation induces sex-specific effects on neuroinflammation, white matter, and behavior.

Exposure to inflammation during pregnancy has been linked to adverse neurodevelopmental consequences for the offspring. One common route through which a developing fetus is exposed to inflammation is with intrauterine inflammation. To that end, we utilized an animal model of intrauterine inflammation (IUI; intrauterine lipopolysaccharide (LPS) administration, 50µg, E15) to assess placental and fetal brain inflammatory responses, white matter integrity, anxiety-related behaviors (elevated zero maze, light dark box, open field), microglial counts, and the CNS cytokine response to an acute injection of LPS in both males and females. These studies revealed that for multiple endpoints (fetal brain cytokine levels, cytokine response to adult LPS challenge) male IUI offspring were uniquely affected by intrauterine inflammation, while for other endpoints (behavior, microglial number) both sexes were similarly affected. These data advance our understanding of sex-specific effects of early life exposure to inflammation in a translationally- relevant model.

Regulation of the Hypothalamic-Pituitary-Adrenocortical Stress Response.

The hypothalamo-pituitary-adrenocortical (HPA) axis is required for stress adaptation. Activation of the HPA axis causes secretion of glucocorticoids, which act on multiple organ systems to redirect energy resources to meet real or anticipated demand. The HPA stress response is driven primarily by neural mechanisms, invoking corticotrophin releasing hormone (CRH) release from hypothalamic paraventricular nucleus (PVN) neurons. Pathways activating CRH release are stressor dependent: reactive responses to homeostatic disruption frequently involve direct noradrenergic or peptidergic drive of PVN neurons by sensory relays, whereas anticipatory responses use oligosynaptic pathways originating in upstream limbic structures. Anticipatory responses are driven largely by disinhibition, mediated by trans-synaptic silencing of tonic PVN inhibition via GABAergic neurons in the amygdala. Stress responses are inhibited by negative feedback mechanisms, whereby glucocorticoids act to diminish drive (brainstem) and promote transsynaptic inhibition by limbic structures (e.g., hippocampus). Glucocorticoids also act at the PVN to rapidly inhibit CRH neuronal activity via membrane glucocorticoid receptors. Chronic stress-induced activation of the HPA axis takes many forms (chronic basal hypersecretion, sensitized stress responses, and even adrenal exhaustion), with manifestation dependent upon factors such as stressor chronicity, intensity, frequency, and modality. Neural mechanisms driving chronic stress responses can be distinct from those controlling acute reactions, including recruitment of novel limbic, hypothalamic, and brainstem circuits. Importantly, an individual's response to acute or chronic stress is determined by numerous factors, including genetics, early life experience, environmental conditions, sex, and age. The context in which stressors occur will determine whether an individual's acute or chronic stress responses are adaptive or maladaptive (pathological).

Chronic social subordination stress modulates glutamic acid decarboxylase (GAD) 67 mRNA expression in central stress circuits.

Chronic social subordination is a well-known precipitant of numerous psychiatric and physiological health concerns. In this study, we examine the effects of chronic social stress in the visible burrow system (VBS) on the expression of glutamic acid decarboxylase (GAD) 67 and brain-derived neurotropic factor (BDNF) mRNA in forebrain stress circuitry. Male rats in the VBS system form a dominance hierarchy, whereby subordinate males exhibit neuroendocrine and physiological profiles characteristic of chronic exposure to stress. We found that social subordination decreases GAD67 mRNA in the peri-paraventricular nucleus region of the hypothalamus and the interfascicular nucleus of the bed nucleus of the stria terminalis (BNST), and increases in GAD67 mRNA in the hippocampus, medial prefrontal cortex, and dorsal medial hypothalamus. Expression of BDNF mRNA increased in the dorsal region of the BNST, but remained unchanged in all other regions examined. Results from this study indicate that social subordination is associated with several region-specific alterations in GAD67 mRNA expression in central stress circuits, whereas changes in the expression of BDNF mRNA are limited to the BNST.