Voluntary Physical Exercise Promotes Ocular Dominance Plasticity in Adult Mouse Primary Visual Cortex

Neurogenin3 Restricts Serotonergic Neuron Differentiation to the Hindbrain

The development of the nervous system is critically dependent on the production of functionally diverse neuronal cell types at their correct locations. In the embryonic neural tube, dorsoventral signaling has emerged as a fundamental mechanism for generating neuronal diversity. In contrast, far less is known about how different neuronal cell types are organized along the rostrocaudal axis. In the developing mouse and chick neural tube, hindbrain serotonergic neurons and spinal glutamatergic V3 interneurons are produced from ventral p3 progenitors, which possess a common transcriptional identity but are confined to distinct anterior–posterior territories. In this study, we show that the expression of the transcription factor Neurogenin3 (Neurog3) in the spinal cord controls the correct specification of p3-derived neurons. Gain- and loss-of-function manipulations in the chick and mouse embryo show that Neurog3 switches ventral progenitors from a serotonergic to V3 differentiation program by repressing Ascl1 in spinal p3 progenitors through a mechanism dependent on Hes proteins. In this way, Neurog3 establishes the posterior boundary of the serotonergic system by actively suppressing serotonergic specification in the spinal cord. These results explain how equivalent p3 progenitors within the hindbrain and the spinal cord produce functionally distinct neuron cell types.

Mammalian Target of Rapamycin's Distinct Roles and Effectiveness in Promoting Compensatory Axonal Sprouting in the Injured CNS

Mammalian target of rapamycin (mTOR) functions as a master sensor of nutrients and energy, and controls protein translation and cell growth. Deletion of phosphatase and tensin homolog (PTEN) in adult CNS neurons promotes regeneration of injured axons in an mTOR-dependent manner. However, others have demonstrated mTOR-independent axon regeneration in different cell types, raising the question of how broadly mTOR regulates axonal regrowth across different systems. Here we define the role of mTOR in promoting collateral sprouting of spared axons, a key axonal remodeling mechanism by which functions are recovered after CNS injury. Using pharmacological inhibition, we demonstrate that mTOR is dispensable for the robust spontaneous sprouting of corticospinal tract axons seen after pyramidotomy in postnatal mice. In contrast, moderate spontaneous axonal sprouting and induced-sprouting seen under different conditions in young adult mice (i.e., PTEN deletion or degradation of chondroitin proteoglycans; CSPGs) are both reduced upon mTOR inhibition. In addition, to further determine the potency of mTOR in promoting sprouting responses, we coinactivate PTEN and CSPGs, and demonstrate that this combination leads to an additive increase in axonal sprouting compared with single treatments. Our findings reveal a developmental switch in mTOR dependency for inducing axonal sprouting, and indicate that PTEN deletion in adult neurons neither recapitulates the regrowth program of postnatal animals, nor is sufficient to completely overcome an inhibitory environment. Accordingly, exploiting mTOR levels by targeting PTEN combined with CSPG degradation represents a promising strategy to promote extensive axonal plasticity in adult mammals.

Accelerated Changes in White Matter Microstructure during Aging: A Longitudinal Diffusion Tensor Imaging Study

It is well established that human brain white matter structure changes with aging, but the timescale and spatial distribution of this change remain uncertain. Cross-sectional diffusion tensor imaging (DTI) studies indicate that, after a period of relative stability during adulthood, there is an accelerated decline in anisotropy and increase in diffusivity values during senescence; and, spatially, results have been discussed within the context of several anatomical frameworks. However, inferring trajectories of change from cross-sectional data can be challenging; and, as yet, there have been no longitudinal reports of the timescale and spatial distribution of age-related white matter change in healthy adults across the adult lifespan. In a longitudinal DTI study of 203 adults between 20 and 84 years of age, we used tract-based spatial statistics to characterize the pattern of annual change in fractional anisotropy, axial diffusivity, radial diffusivity, and mean diffusivity and examined whether there was an acceleration of change with age. We found extensive and overlapping significant annual decreases in fractional anisotropy, and increases in axial diffusivity, radial diffusivity, and mean diffusivity. Spatially, results were consistent with inferior-to-superior gradients of lesser-to-greater vulnerability. Annual change increased with age, particularly within superior regions, with age-related decline estimated to begin in the fifth decade. Charting white matter microstructural changes in healthy aging provides essential context to clinical studies, and future studies should compare age trajectories between healthy participants and at-risk populations and also explore the relationship between DTI rates of change and cognitive decline.

Noradrenergic Plasticity of Olfactory Sensory Neuron Inputs to the Main Olfactory Bulb

Sensory responses are modulated by internal factors including attention, experience, and brain state. This is partly due to fluctuations in neuromodulatory input from regions such as the noradrenergic locus ceruleus (LC) in the brainstem. LC activity changes with arousal and modulates sensory processing, cognition, and memory. The main olfactory bulb (MOB) is richly targeted by LC fibers and noradrenaline profoundly influences MOB circuitry and odor-guided behavior. Noradrenaline-dependent plasticity affects the output of the MOB; however. it is unclear whether noradrenergic plasticity also affects the input to the MOB from olfactory sensory neurons (OSNs) in the glomerular layer. Noradrenergic terminals are found in the glomerular layer, but noradrenaline receptors do not seem to acutely modulate OSN terminals in vitro. We investigated whether noradrenaline induces plasticity at the glomerulus. We used wide-field optical imaging to measure changes in odor responses following electrical stimulation of LC in anesthetized mice. Surprisingly, odor-evoked intrinsic optical signals at the glomerulus were persistently weakened after LC activation. Calcium imaging selectively from OSNs confirmed that this effect was due to suppression of presynaptic input and was prevented by noradrenergic antagonists. Finally, suppression of responses to an odor did not require precise coincidence of the odor with LC activation. However, suppression was intensified by LC activation in the absence of odors. We conclude that noradrenaline release from LC has persistent effects on odor processing already at the first synapse of the main olfactory system. This mechanism could contribute to arousal-dependent memories.

Sexual Differentiation of the Brain Requires Perinatal Kisspeptin-GnRH Neuron Signaling

Sex differences in brain function underlie robust differences between males and females in both normal and disease states. Although alternative mechanisms exist, sexual differentiation of the male mammalian brain is initiated predominantly by testosterone secreted by the testes during the perinatal period. Despite considerable advances in understanding how testosterone and its metabolite estradiol sexually differentiate the brain, little is known about the mechanism that generates the male-specific perinatal testosterone surge. In mice, we show that a male-specific activation of GnRH neurons occurs 0–2 h following birth and that this correlates with the male-specific surge of testosterone occurring up to 5 h after birth. The necessity of GnRH signaling for the sexually differentiating effects of the perinatal testosterone surge was demonstrated by the persistence of female-like brain characteristics in adult male, GnRH receptor knock-out mice. Kisspeptin neurons have recently been identified to be potent, direct activators of GnRH neurons. We demonstrate that a population of kisspeptin neurons appears in the preoptic area of only the male between E19 and P1. The importance of kisspeptin inputs to GnRH neurons for the process of sexual differentiation was demonstrated by the lack of a normal neonatal testosterone surge, and disordered brain sexual differentiation of male mice in which the kisspeptin receptor was deleted selectively from GnRH neurons. These observations demonstrate the necessity of perinatal GnRH signaling for driving brain sexual differentiation and indicate that kisspeptin inputs to GnRH neurons are essential for this process to occur.

Control of Food Intake and Energy Expenditure by Nos1 Neurons of the Paraventricular Hypothalamus

The paraventricular nucleus of the hypothalamus (PVH) contains a heterogeneous cluster of Sim1-expressing cell types that comprise a major autonomic output nucleus and play critical roles in the control of food intake and energy homeostasis. The roles of specific PVH neuronal subtypes in energy balance have yet to be defined, however. The PVH contains nitric oxide synthase-1 (Nos1)-expressing (Nos1^PVH) neurons of unknown function; these represent a subset of the larger population of Sim1-expressing PVH (Sim1^PVH) neurons. To determine the role of Nos1^PVH neurons in energy balance, we used Cre-dependent viral vectors to both map their efferent projections and test their functional output in mice. Here we show that Nos1^PVH neurons project to hindbrain and spinal cord regions important for food intake and energy expenditure control. Moreover, pharmacogenetic activation of Nos1^PVH neurons suppresses feeding to a similar extent as Sim1^PVH neurons, and increases energy expenditure and activity. Furthermore, we found that oxytocin-expressing PVH neurons (OXT^PVH) are a subset of Nos1^PVH neurons. OXT^PVH cells project to preganglionic, sympathetic neurons in the thoracic spinal cord and increase energy expenditure upon activation, though not to the same extent as Nos1^PVH neurons; their activation fails to alter feeding, however. Thus, Nos1^PVH neurons promote negative energy balance through changes in feeding and energy expenditure, whereas OXT^PVH neurons regulate energy expenditure alone, suggesting a crucial role for non-OXT Nos1^PVH neurons in feeding regulation.