Brain plasticity is dynamically regulated across the life span, peaking during windows of early life. Typically assessed in the physiological range of milliseconds (real time), these trajectories are also influenced on the longer timescales of developmental time (nurture) and evolutionary time (nature), which shape neural architectures that support plasticity. Properly sequenced critical periods of circuit refinement build up complex cognitive functions, such as language, from more primary modalities. Here, we consider recent progress in the biological basis of critical periods as a unifying rubric for understanding plasticity across multiple timescales. Notably, the maturation of parvalbumin-positive (PV) inhibitory neurons is pivotal. These fast-spiking cells generate gamma oscillations associated with critical period plasticity, are sensitive to circadian gene manipulation, emerge at different rates across brain regions, acquire perineuronal nets with age, and may be influenced by epigenetic factors over generations. These features provide further novel insight into the impact of early adversity and neurodevelopmental risk factors for mental disorders.

The presence of large-amplitude, slow waves in the EEG is a primary characteristic that distinguishes cerebral activity during sleep from that which occurs during wakefulness. Although sleepactive neurons have been identified in other brain areas, neurons that are specifically activated during slow-wave sleep have not previously been described in the cerebral cortex. We have identified a population of cells in the cortex that is activated during sleep in three mammalian species. These cortical neurons are a subset of GABAergic interneurons that express neuronal NOS (nNOS). Because Fos expression in these sleep-active, nNOS-immunoreactive (nNOS-ir) neurons parallels changes in the intensity of slow-wave activity in the EEG, and these neurons are innvervated by neurotransmitter systems previously implicated in sleep/wake control, cortical nNOS-ir neurons may be part of the neurobiological substrate that underlies homeostatic sleep regulation.Fos ͉ interneuron ͉ neuronal NOS ͉ sleep deprivation ͉ wakefulness S leep is well known to have recuperative properties (1) and to facilitate performance of learned behaviors (2, 3); conversely, sleep deprivation results in cognitive and performance deficits (4). The presence of large-amplitude, slow waves in the EEG is the hallmark that distinguishes cerebral activity during sleep from wakefulness. Because the intensity of slow waves measured in the delta range of the EEG (1.0-4.0 Hz) appears to be homeostatically regulated and proportional to prior wake duration (5), slow-wave activity (SWA) has been hypothesized to be associated with the restorative function of sleep and with synaptic plasticity (2, 3, 6).The neural circuitry underlying SWA involves a corticothalamocortical loop and interplay between a hyperpolarizationactivated cation current (I h ) and a low-threshold Ca 2ϩ current (I t ) in thalamocortical neurons (7,8). It is currently unknown whether the cerebral cortex is an active participant or simply a passive conveyor of sleep history-dependent SWA dynamics. Identification of a discrete sleep-active population of cortical neurons, such as those in the basal forebrain (BF) (9) and the preoptic-anterior hypothalamus (POAH) (10-13), would help distinguish between these alternatives.In experiments conducted in three mammalian species, we found that GABAergic interneurons expressing the enzyme neuronal NOS (nNOS) are activated both during spontaneous sleep and during recovery sleep (RS) after sleep deprivation (SD). The proportion of nNOS-immunoreactive (nNOS-ir) neurons that are activated during sleep is correlated with a measure of SWA intensity known as ''delta energy' ' (14, 15). Because sleep-active, nNOS-ir neurons are innervated by neurotransmitter systems previously implicated in sleep/wake control, cortical nNOS-ir neurons may be a previously unrecognized cell type involved in SWA and part of the neurobiological substrate that underlies homeostatic sleep regulation. Results Fos Expression Is Increased in Cortical nNOS Neurons During RS.Fos expression has previ...

Background Posttraumatic stress disorder (PTSD) is a prevalent psychiatric disorder precipitated by exposure to extreme traumatic stress. Yet, most individuals exposed to traumatic stress do not develop PTSD and may be considered psychologically resilient. The neural circuits involved in susceptibility or resiliency to PTSD remain unclear, but clinical evidence implicates changes in the noradrenergic system. Methods An animal model of PTSD called Traumatic Experience with Reminders of Stress (TERS) was developed by exposing C57BL/6 mice to a single shock (2mA, 10sec) followed by exposure to six contextual1-minute reminders of the shock overa 25-dayperiod. Acoustic startle response (ASR) testing before the shock and after the last reminder allowed experimenters to separate the shocked mice into two cohorts: mice that developed a greatly increased ASR (TERS-susceptible mice) and mice that did not (TERS-resilient mice). Results Aggressive and social behavioral correlates of PTSD increased in TERS-susceptible mice but not in TERS-resilient mice or control mice. Characterization of c-Fos expression in stress-related brain regions revealed that TERS-susceptible and TERS-resilient mice displayed divergent brain activation following swim stress compared with control mice. Pharmacological activation of noradrenergic inhibitory autoreceptors or blockade of postsynaptic α1-adrenoreceptors normalized ASR, aggression, and social interaction in TERS-susceptible mice. The TERS-resilient, but not TERS-susceptible, mice showed a trend toward decreased behavioral responsiveness to noradrenergic autoreceptor blockade compared with control mice. Conclusions These data implicate the noradrenergic system as a possible site of pathological and perhaps also adaptive plasticity in response to traumatic stress.

The Nougaret form of dominant stationary night blindness is linked to a G38D mutation in the rod transducin-␣ subunit (T␣). In this study, we have examined the mechanism of Nougaret night blindness using transgenic mice expressing T␣G38D. The biochemical, electrophysiological, and vision-dependent behavioral analyses of the mouse model revealed a unique phenotype of reduced rod sensitivity, impaired activation, and slowed recovery of the phototransduction cascade. Two key deficiencies in T␣G38D function, its poor ability to activate PDE6 (cGMP phosphodiesterase) and decreased GTPase activity, are found to be the major mechanisms altering visual signaling in transgenic mice. Despite these defects, rod-mediated sensitivity in heterozygous mice is not decreased to the extent seen in heterozygous Nougaret patients.