Neural decoding reveals specialized kinematic tuning after an abrupt cortical transition.

The primary motor cortex (M1) exhibits a protracted period of development, including the development of a sensory representation long before motor outflow emerges. In rats, this representation is present by postnatal day (P) 8, when M1 activity is "discontinuous." Here, we ask how the representation changes upon the transition to "continuous" activity at P12. We use neural decoding to predict forelimb movements from M1 activity and show that a linear decoder effectively predicts limb movements at P8 but not at P12; instead, a nonlinear decoder better predicts limb movements at P12. The altered decoder performance reflects increased complexity and uniqueness of kinematic information in M1. We next show that M1's representation at P12 is more susceptible to "lesioning" of inputs and "transplanting" of M1's encoding scheme from one pup to another. Thus, the emergence of continuous M1 activity signals the developmental onset of more complex, informationally sparse, and individualized sensory representations.

Sensory Coding of Limb Kinematics in Motor Cortex across a Key Developmental Transition.

Primary motor cortex (M1) undergoes protracted development in mammals, functioning initially as a sensory structure. Throughout the first postnatal week in rats, M1 is strongly activated by self-generated forelimb movements-especially by the twitches that occur during active sleep. Here, we quantify the kinematic features of forelimb movements to reveal receptive-field properties of individual units within the forelimb region of M1. At postnatal day 8 (P8), nearly all units were strongly modulated by movement amplitude, especially during active sleep. By P12, only a minority of units continued to exhibit amplitude tuning, regardless of behavioral state. At both ages, movement direction also modulated M1 activity, though to a lesser extent. Finally, at P12, M1 population-level activity became more sparse and decorrelated, along with a substantial alteration in the statistical distribution of M1 responses to limb movements. These findings reveal a transition toward a more complex and informationally rich representation of movement long before M1 develops its motor functionality.SIGNIFICANCE STATEMENT Primary motor cortex (M1) plays a fundamental role in the generation of voluntary movements and motor learning in adults. In early development, however, M1 functions as a prototypical sensory structure. Here, we demonstrate in infant rats that M1 codes for the kinematics of self-generated limb movements long before M1 develops its capacity to drive movements themselves. Moreover, we identify a key transition during the second postnatal week in which M1 activity becomes more informationally complex. Together, these findings further delineate the complex developmental path by which M1 develops its sensory functions in support of its later-emerging motor capacities.

Twitches emerge postnatally during quiet sleep in human infants and are synchronized with sleep spindles.

In humans and other mammals, the stillness of sleep is punctuated by bursts of rapid eye movements (REMs) and myoclonic twitches of the limbs.1 Like the spontaneous activity that arises from the sensory periphery in other modalities (e.g., retinal waves),2 sensory feedback arising from twitches is well suited to drive activity-dependent development of the sensorimotor system.3 It is partly because of the behavioral activation of REM sleep that this state is also called active sleep (AS), in contrast with the behavioral quiescence that gives quiet sleep (QS)-the second major stage of sleep-its name. In human infants, for which AS occupies 8 h of each day,4 twitching helps to identify the state;5-8 nonetheless, we know little about the structure and functions of twitching across development. Recently, in sleeping infants,9 we documented a shift in the temporal expression of twitching beginning around 3 months of age that suggested a qualitative change in how twitches are produced. Here, we combine behavioral analysis with high-density electroencephalography (EEG) to demonstrate that this shift reflects the emergence of limb twitches during QS. Twitches during QS are not only unaccompanied by REMs, but they also occur synchronously with sleep spindles, a hallmark of QS. As QS-related twitching increases with age, sleep spindle rate also increases along the sensorimotor strip. The emerging synchrony between subcortically generated twitches and cortical oscillations suggests the development of functional connectivity among distant sensorimotor structures, with potential implications for detecting and explaining atypical developmental trajectories.

Self-Generated Whisker Movements Drive State-Dependent Sensory Input to Developing Barrel Cortex.

Cortical development is an activity-dependent process [1-3]. Regarding the role of activity in the developing somatosensory cortex, one persistent debate concerns the importance of sensory feedback from self-generated movements. Specifically, recent studies claim that cortical activity is generated intrinsically, independent of movement [3, 4]. However, other studies claim that behavioral state moderates the relationship between movement and cortical activity [5-7]. Thus, perhaps inattention to behavioral state leads to failures to detect movement-driven activity [8]. Here, we resolve this issue by associating local field activity (i.e., spindle bursts) and unit activity in the barrel cortex of 5-day-old rats with whisker movements during wake and myoclonic twitches of the whiskers during active (REM) sleep. Barrel activity increased significantly within 500 ms of whisker movements, especially after twitches. Also, higher-amplitude movements were more likely to trigger barrel activity; when we controlled for movement amplitude, barrel activity was again greater after a twitch than a wake movement. We then inverted the analysis to assess the likelihood that increases in barrel activity were preceded within 500 ms by whisker movements: at least 55% of barrel activity was attributable to sensory feedback from whisker movements. Finally, when periods with and without movement were compared, 70%-75% of barrel activity was movement related. These results confirm the importance of sensory feedback from movements in driving activity in sensorimotor cortex and underscore the necessity of monitoring sleep-wake states to ensure accurate assessments of the contributions of the sensory periphery to activity in developing somatosensory cortex.

A Basal Forebrain Site Coordinates the Modulation of Endocrine and Behavioral Stress Responses via Divergent Neural Pathways.

UNLABELLED: The bed nuclei of the stria terminalis (BST) are critically important for integrating stress-related signals between the limbic forebrain and hypothalamo-pituitary-adrenal (HPA) effector neurons in the paraventricular hypothalamus (PVH). Nevertheless, the circuitry underlying BST control over the stress axis and its role in depression-related behaviors has remained obscure. Utilizing optogenetic approaches in rats, we have identified a novel role for the anteroventral subdivision of BST in the coordinated inhibition of both HPA output and passive coping behaviors during acute inescapable (tail suspension, TS) stress. Follow-up experiments probed axonal pathways emanating from the anteroventral BST which accounted for separable endocrine and behavioral functions subserved by this cell group. The PVH and ventrolateral periaqueductal gray were recipients of GABAergic outputs from the anteroventral BST that were necessary to restrain stress-induced HPA activation and passive coping behavior, respectively, during TS and forced swim tests. In contrast to other BST subdivisions implicated in anxiety-like responses, these results direct attention to the anteroventral BST as a nodal point in a stress-modulatory network for coordinating neuroendocrine and behavioral coping responses, wherein impairment could account for core features of stress-related mood disorders. SIGNIFICANCE STATEMENT: Dysregulation of the neural pathways modulating stress-adaptive behaviors is implicated in stress-related psychiatric illness. While aversive situations activate a network of limbic forebrain regions thought to mediate such changes, little is known about how this information is integrated to orchestrate complex stress responses. Here we identify novel roles for the anteroventral bed nuclei of the stria terminalis in inhibiting both stress hormone output and passive coping behavior via divergent projections to regions of the hypothalamus and midbrain. Inhibition of these projections produced features observed with rodent models of depression, namely stress hormone hypersecretion and increased passive coping behavior, suggesting that dysfunction in these networks may contribute to expression of pathological changes in stress-related disorders.

Prolonged corticosterone exposure induces dendritic spine remodeling and attrition in the rat medial prefrontal cortex.

The stress-responsive hypothalamo-pituitary-adrenal (HPA) axis plays a central role in promoting adaptations acutely, whereas adverse effects on physiology and behavior following chronic challenges may result from overactivity of this system. Elevations in glucocorticoids, the end-products of HPA activation, play roles in adaptive and maladaptive processes by targeting cognate receptors throughout neurons in limbic cortical networks to alter synaptic functioning. Because previous work has shown that chronic stress leads to functionally relevant regressive alterations in dendritic spine shape and number in pyramidal neurons in the medial prefrontal cortex (mPFC), this study examines the capacity of sustained increases in circulating corticosterone (B) alone to alter dendritic spine morphology and density in this region. Subcutaneous B pellets were implanted in rats to provide continuous exposure to levels approximating the circadian mean or peak of the steroid for 1, 2, or 3 weeks. Pyramidal neurons in the prelimbic area of the mPFC were selected for intracellular fluorescent dye filling, followed by high-resolution three-dimensional imaging and analysis of dendritic arborization and spine morphometry. Two or more weeks of B exposure decreased dendritic spine volume in the mPFC, whereas higher dose exposure of the steroid resulted in apical dendritic retraction and spine loss in the same cell population, with thin spine subtypes showing the greatest degree of attrition. Finally, these structural alterations were noted to persist following a 3-week washout period and corresponding restoration of circadian HPA rhythmicity. These studies suggest that prolonged disruptions in adrenocortical functioning may be sufficient to induce enduring regressive structural and functional alterations in the mPFC. J. Comp. Neurol. 524:3729-3746, 2016. © 2016 Wiley Periodicals, Inc.

The Contingency of Cocaine Administration Accounts for Structural and Functional Medial Prefrontal Deficits and Increased Adrenocortical Activation.

The prelimbic region (PL) of the medial prefrontal cortex (mPFC) is implicated in the relapse of drug-seeking behavior. Optimal mPFC functioning relies on synaptic connections involving dendritic spines in pyramidal neurons, whereas prefrontal dysfunction resulting from elevated glucocorticoids, stress, aging, and mental illness are each linked to decreased apical dendritic branching and spine density in pyramidal neurons in these cortical fields. The fact that cocaine use induces activation of the stress-responsive hypothalamo-pituitary-adrenal axis raises the possibility that cocaine-related impairments in mPFC functioning may be manifested by similar changes in neuronal architecture in mPFC. Nevertheless, previous studies have generally identified increases, rather than decreases, in structural plasticity in mPFC after cocaine self-administration. Here, we use 3D imaging and analysis of dendritic spine morphometry to show that chronic cocaine self-administration leads to mild decreases of apical dendritic branching, prominent dendritic spine attrition in PL pyramidal neurons, and working memory deficits. Importantly, these impairments were largely accounted for in groups of rats that self-administered cocaine compared with yoked-cocaine- and saline-matched counterparts. Follow-up experiments failed to demonstrate any effects of either experimenter-administered cocaine or food self-administration on structural alterations in PL neurons. Finally, we verified that the cocaine self-administration group was distinguished by more protracted increases in adrenocortical activity compared with yoked-cocaine- and saline-matched controls. These studies suggest a mechanism whereby increased adrenocortical activity resulting from chronic cocaine self-administration may contribute to regressive prefrontal structural and functional plasticity. SIGNIFICANCE STATEMENT: Stress, aging, and mental illness are each linked to decreased prefrontal plasticity. Here, we show that chronic cocaine self-administration in rats leads to decrements in medial prefrontal structural and functional plasticity. Notably, these impairments were largely accounted for in rats that self-administered cocaine compared with yoked counterparts. Moreover, we verified previous reports showing that adrenocortical output is augmented by cocaine administration and is more protracted in rats that were permitted to receive the drug contingently instead of passively. These studies suggest that increased adrenocortical activity resulting from cocaine self-administration may contribute to regressive prefrontal structural and functional plasticity.