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Frequency discrimination learning is often accompanied by an expansion of the functional region corresponding to the target frequency within the auditory cortex. Although the perceptual significance of this plastic functional reorganization remains debated, greater cortical representation is generally thought to improve perception for a stimulus. Recently, the ability to expand functional representations through passive sound experience has been demonstrated in adult rats, suggesting that it may be possible to design passive sound exposures to enhance specific perceptual abilities in adulthood. To test this hypothesis, we exposed adult female Long–Evans rats to 2 weeks of moderate-intensity broadband white noise followed by 1 week of 7 kHz tone pips, a paradigm that results in the functional over-representation of 7 kHz within the adult tonotopic map. We then tested the ability of exposed rats to identify 7 kHz among distractor tones on an adaptive tone discrimination task. Contrary to our expectations, we found that map expansion impaired frequency discrimination and delayed perceptual learning. Rats exposed to noise followed by 15 kHz tone pips were not impaired at the same task. Exposed rats also exhibited changes in auditory cortical responses consistent with reduced discriminability of the exposure tone. Encouragingly, these deficits were completely recovered with training. Our results provide strong evidence that map expansion alone does not imply improved perception. Rather, plastic changes in frequency representation induced by bottom-up processes can worsen perceptual faculties, but because of the very nature of plasticity these changes are inherently reversible.SIGNIFICANCE STATEMENTThe potent ability of our acoustic environment to shape cortical sensory representations throughout life has led to a growing interest in harnessing both passive sound experience and operant perceptual learning to enhance mature cortical function. We use sound exposure to induce targeted expansions in the adult rat tonotopic map and find that these bottom-up changes unexpectedly impair performance on an adaptive tone discrimination task. Encouragingly, however, we also show that training promotes the recovery of electrophysiological measures of reduced neural discriminability following sound exposure. These results provide support for future neuroplasticity-based treatments that take into account both the sensory statistics of our external environment and perceptual training strategies to improve learning and memory in the adult auditory system.

Sensory experience during early developmental critical periods (CPs) has profound and long-lasting effects on cortical sensory processing perduring well into adulthood. Although recent evidence has shown that reducing cortical inhibition during adulthood reinstates CP plasticity, the precise cellular mechanisms are not well understood. Here, we show that chemogenetic inactivation of parvalbumin-positive (PV + ) interneurons is sufficient to reinstate CP plasticity in the adult auditory cortex. Bidirectional manipulation of PV + cell activity affected neuronal spectral and sound intensity selectivity and, in the case of PV + interneuron inactivation, was mirrored by anatomical changes in PV and associated perineuronal net expression. These findings underscore the importance of sustained PV-mediated inhibitory neurotransmission throughout life and highlight the potential of chemogenetic approaches for harnessing cortical plasticity with the ultimate goal of aiding recovery from brain injury or disease.

BackgroundTo investigate the association of plasma pTau181, assessed with a new immunoassay, with neurodegeneration of white matter and gray matter cross-sectionally and longitudinally, in aging and Alzheimer’s disease.MethodsObservational data was obtained from the Alzheimer’s Disease Neuroimaging Initiative, in which participants underwent plasma assessment and magnetic resonance imaging. Based on their clinical diagnosis, participants were classified as cognitively unimpaired and cognitively impaired. Linear regressions and linear mixed-effect models were used to test the cross-sectional and longitudinal associations between baseline plasma pTau181 and neurodegeneration using voxel-based morphometry.ResultsWe observed a negative correlation at baseline between plasma pTau181 and gray matter volume in cognitively unimpaired individuals. In cognitively impaired individuals, we observed a negative association between plasma pTau181 and both gray and white matter volume. In longitudinal analyses conducted in the cognitively unimpaired group, plasma pTau181 was negatively correlated with gray matter volume, starting 36 months after baseline assessments. Finally, in cognitively impaired individuals, plasma pTau181 concentrations were negatively correlated with both gray and white matter volume as early as 12 months after baseline, and neurodegeneration increased in an incremental manner until 48 months.ConclusionsHigher levels of plasma pTau181 correlate with neurodegeneration and predict further brain atrophy in aging and Alzheimer’s disease. Plasma pTau181 may be useful in predicting AD-related neurodegeneration, comparable to positron emission tomography or cerebrospinal fluid assessment with high specificity for AD neurodegeneration.

Brain plasticity is maximal at specific time windows during early development known as critical periods (CPs), during which sensory experience is necessary to establish optimal cortical representations of the surrounding environment. After CP closure, a range of functional and structural elements prevent passive experience from eliciting significant plastic changes in the brain. The transition from a plastic to a more fixed state is advantageous as it allows for the sequential consolidation and retention of new and more complex perceptual, motor, and cognitive functions. However, the formation of stable neural representations may pose limitations on future revisions to the circuitry. If sensory experience is abnormal or absent during this time, it can have profound effects on sensory representations in adulthood, resulting in quasi-permanent adaptations that can make it nearly impossible to learn certain skills or process certain stimulus properties later on in life. This chapter begins with a brief introduction to experience-dependent plasticity throughout the lifespan (Section Introduction). Next, we define what constitutes a CP (Section What Are Critical Periods?) and review some of the key CPs in the visual and auditory systems (Section Key Critical Periods of Sensory Systems). We then discuss the mechanisms whereby cortical plasticity is regulated both locally and through neuromodulatory systems (Section How Are Critical Periods Regulated?). Finally, we highlight studies showing that CPs can be extended beyond their normal epochs, closed prematurely, or reopened during adult life by merely altering sensory inputs (Section Timing of Critical Periods: Can CP Plasticity Be Extended, Limited, or Reactivated?).

Nowadays, the majority of the progress in the development of implantable neuroprostheses has been achieved by improving the knowledge of brain functions so as to restore sensorial impairments. Intracortical microstimulation (ICMS) is a widely used technique to investigate site-specific cortical responses to electrical stimuli. Herein, we investigated the neural modulation induced in the primary auditory cortex (A1) by an acousto-electric transduction of ultrasonic signals using a bio-inspired intracortical microstimulator. The developed electronic system emulates the transduction of ultrasound signals in the cochlea, providing bio-inspired electrical stimuli. Firstly, we identified the receptive fields in the primary auditory cortex devoted to encoding ultrasonic waves at different frequencies, mapping each area with neurophysiological patterns. Subsequently, the activity elicited by bio-inspired ICMS in the previously identified areas, bypassing the sense organ, was investigated. The observed evoked response by microstimulation resulted as highly specific to the stimuli, and the spatiotemporal dynamics of neural oscillatory activity in the alpha, beta, and gamma waves were related to the stimuli preferred by the neurons at the stimulated site. The alpha waves modulated cortical excitability only during the activation of the specific tonotopic neuronal populations, inhibiting neural responses in unrelated areas. Greater neuronal activity in the posterior area of A1 was observed in the beta band, whereas a gamma rhythm was induced in the anterior A1. The results evidence that the proposed bio-inspired acousto-electric ICMS triggers high-frequency oscillations, encoding information about the stimulation sites and involving a large-scale integration in the brain.

Evidence indicates that neuroplasticity-based cognitive training can improve cognition in patients with schizophrenia, but the individual response to training varies greatly between subjects. Hence, there is a need to understand the neurological underpinnings of cognitive training to reveal predictors of treatment response. D-serine is a crucial modulator of neuroplasticity, and decreased levels of D-serine may contribute to deficits in neuroplasticity in schizophrenia. Interestingly, we observed that training mice to identify auditory oddballs increased extracellular levels of D-serine in the hippocampus during training. Serine racemase (Srr) is the only source of brain D-serine; thus, it is possible that Srr may mediate the response to training. To test this hypothesis, we trained mice that have a mutated version of Srr (SrrY269*/SrrY269*) and reduced levels of D-serine in the same auditory training. SrrY269*/SrrY269* mice showed decreased performance during auditory training (defined as the capacity to discriminate an oddball during a sequence of tones). Importantly, auditory training improved prepulse inhibition (PPI) in SrrY269*/SrrY269* but not in wild-type mice. Finally, D-serine (100 mg/kg i.p.) given 30 min before training sessions to SrrY269*/SrrY269* mice improved training performance, but it did not enhance PPI. Taken together, our results show that D-serine is involved in the response to neuroplasticity-based auditory training and that PPI deficits can be improved by auditory oddball training even in the presence of neuroplasticity deficits.

Brain plasticity is maximal at specific time windows during early development known as critical periods (CPs), during which sensory experience is necessary to establish optimal cortical representations of the surrounding environment. After CP closure, a range of functional and structural elements prevent passive experience from eliciting significant plastic changes in the brain. The transition from a plastic to a more fixed state is advantageous as it allows for the sequential consolidation and retention of new and more complex perceptual, motor, and cognitive functions. However, the formation of stable neural representations may pose limitations on future revisions to the circuitry. If sensory experience is abnormal or absent during this time, it can have profound effects on sensory representations in adulthood, resulting in quasi-permanent adaptations that can make it nearly impossible to learn certain skills or process certain stimulus properties later on in life. This chapter begins with a brief introduction to experience-dependent plasticity throughout the lifespan (Section Introduction). Next, we define what constitutes a CP (Section What Are Critical Periods?) and review some of the key CPs in the visual and auditory systems (Section Key Critical Periods of Sensory Systems). We then discuss the mechanisms whereby cortical plasticity is regulated both locally and through neuromodulatory systems (Section How Are Critical Periods Regulated?). Finally, we highlight studies showing that CPs can be extended beyond their normal epochs, closed prematurely, or reopened during adult life by merely altering sensory inputs (Section Timing of Critical Periods: Can CP Plasticity Be Extended, Limited, or Reactivated?).

The prolonged masking of auditory inputs with white noise has been shown to reopen the critical period for spectral tuning in the adult rat auditory cortex. Here, we argue that the masking of salient temporal inputs in particular is responsible for changes in neuronal activity that lead to this experience-dependent plasticity. We tested this hypothesis by passively exposing adult rats to 2 weeks of amplitude-modulated (AM) white noise with different modulation depths from 0% (no modulation) to 100% (strong modulation). All exposed rats displayed evidence of cortical plasticity as measured by receptive field bandwidths, tonotopic gradients, and synchronization during spontaneous activity. However, this plasticity was fundamentally different in nature for rats exposed to unmodulated noise, as a second passive exposure to pure tones elicited tonotopic reorganization in rats exposed to 0% AM noise only. Detection of c-FOS expression in excitatory and inhibitory cells through post-mortem immunohistochemistry also revealed different patterns of cellular activation depending on modulation depth. Together, these results indicate that the absence of temporal modulation promotes noise-induced plasticity in the adult auditory cortex and suggest an important and continuous role for temporally salient inputs in the maintenance of mature auditory circuits.

Background Cases of sensory loss provide an excellent model to study the plastic nature of cortical sensory systems. Models of reversible sensory loss are particularly useful for establishing the timeline of various critical periods for cortical plasticity. However, there currently is an absence of adequate methods to produce reversible hearing loss in neonatal and developing rodents. New method We propose a novel and reversible adaptation of an existing surgical technique—external auditory canal ligation (EACL)—that produces a reliable and moderate hearing loss. Results Auditory brainstem responses (ABRs) were used to measure both the magnitude of the hearing loss induced by EACL and the auditory thresholds following hearing restoration. The EACL and reopening procedures, as assessed by visual inspection, had success rates of 81% and 78%, respectively. The average hearing thresholds, as assessed with ABRs, increased by nearly 40 decibels across all tested frequencies. Hearing thresholds returned to normal levels following the reopening procedure. Comparison with existing methods Our procedure yields similar benefits to other methods, such as producing a reliable and moderate hearing loss that is entirely reversible. Furthermore, to our knowledge, it is the first that can be performed in neonatal rodents, thus allowing researchers the opportunity to assess the effects of sensory loss on behavior and cortical neurophysiology during developmental critical periods. Conclusion Our modified technique of reversible external auditory canal ligation offers an easy, and reliable method to induce a transient state of hearing loss that mimics naturally occurring congenital conductive hearing loss.

During early developmental windows known as critical periods (CPs) of plasticity, passive alterations in the quality and quantity of sensory inputs are sufficient to induce profound and long-lasting distortions in cortical sensory representations. With CP closure, those representations are stabilized, a process requiring the maturation of inhibitory networks and the maintenance of sufficient GABAergic tone in the cortex. In humans and rodents, however, cortical inhibition progressively decreases with advancing age, raising the possibility that the regulation of plasticity could be altered in older individuals. Here we tested the hypothesis that aging results in a destabilization of sensory representations and maladaptive dysregulated plasticity in the rat primary auditory cortex (A1). Consistent with this idea, we found that passive tone exposure is sufficient to distort frequency tuning in the A1 of older but not younger adult rats. However, we also found that these passive distortions decayed rapidly, indicating an ongoing instability of A1 tuning in the aging cortex. These changes were associated with a decrease in GABA neurotransmitter concentration and a reduction in parvalbumin and perineuronal net expression in the cortex. Finally, we show that artificially increasing GABA tone in the aging A1 is sufficient to restore representational stability and improve the retention of learning.

Schizophrenia is a complex brain syndrome characterized by an array of positive symptoms (delusions, hallucinations, disorganized speech), negative symptoms (alogia, apathy, avolition) and cognitive impairments (memory, executive functions). Although investigations of the cognitive deficits in schizophrenia have primarily concentrated on disturbances affecting higher-order cognitive processes, there is an increasing realization that schizophrenia also affects early sensory processing, which might, in fact, play a significant role in the development of higher-order cognitive impairments. Recent evidence suggests that many of these early sensory processing impairments possibly arise from a dysregulation of plasticity regulators in schizophrenia, resulting in either reduced plasticity or excessive unregulated plasticity. The purpose of the present manuscript is to provide a concise overview of how the dysregulation of cortical plasticity mechanisms contributes to schizophrenia symptoms with an emphasis on auditory dysplasticity and to discuss its relevance for treatment outcomes. The idea that plasticity mechanisms are not constrained only within sensitive periods suggests that many functional properties of sensory neurons can be altered throughout the lifetime.

SummaryAging is associated with deficits in the ability to ignore distractions, which has not yet been remediated by any neurotherapeutic approach. Here, in parallel auditory experiments with older rats and humans, we evaluated a targeted cognitive training approach that adaptively manipulated distractor challenge. Training resulted in enhanced discrimination abilities in the setting of irrelevant information in both species that was driven by selectively diminished distraction-related errors. Neural responses to distractors in auditory cortex were selectively reduced in both species, mimicking the behavioral effects. Sensory receptive fields in trained rats exhibited improved spectral and spatial selectivity. Frontal theta measures of top-down engagement with distractors were selectively restrained in trained humans. Finally, training gains generalized to group and individual level benefits in aspects of working memory and sustained attention. Thus, we demonstrate converging cross-species evidence for training-induced selective plasticity of distractor processing at multiple neural scales, benefitting distractor suppression and cognitive control.Video Abstract

Temporal lobe epilepsy (TLE) is typically described as a neurologic disorder affecting a cerebral network comprising the hippocampus proper and several anatomically related extrahippocampal regions. A new level of complexity was recently added to the study of this disorder by the evidence that TLE also appears to chronically alter the activity of several brain-wide neural networks involved in the control of higher order brain functions and not traditionally linked to epilepsy. Recently developed brain imaging techniques such as functional magnetic resonance imaging (fMRI) analysis of resting state connectivity, have greatly contributed to these observations by allowing the precise characterization of several brain networks with distinct functional signatures in the resting brain, and therefore also known as "resting state networks." These significant advances in imaging represent an opportunity to investigate the still elusive origins of the disabling cognitive and psychiatric manifestations of TLE, and could have important implications for its pathophysiology and, perhaps, its therapy. Herein we review recent studies in this field by focusing on resting state networks that have been implicated in the pathophysiology of psychiatric disorders and cognitive impairment in patients with epilepsy: the default mode network, the attention network, and the reward/emotion network.

We used the rat primary auditory cortex (A1) as a model to probe the effects of cholinergic enhancement on perceptual learning and auditory processing mechanisms in both young and old animals. Rats learned to perform a two-tone frequency discrimination task over the course of two weeks, combined with either the administration of a cholinesterase inhibitor or saline. We found that while both age groups learned the task more quickly through cholinergic enhancement, the young did so by improving target detection, whereas the old did so by inhibiting erroneous responses to nontarget stimuli. We also found that cholinergic enhancement led to marked functional and structural changes within A1 in both young and old rats. Importantly, we found that several functional changes observed in the old rats, particularly those relating to the processing and inhibition of nontargets, produced cortical processing features that resembled those of young untrained rats more so than those of older adult rats. Overall, these findings demonstrate that combining auditory training with neuromodulation of the cholinergic system can restore many of the auditory cortical functional deficits observed as a result of normal aging and add to the growing body of evidence demonstrating that many age-related perceptual and neuroplastic changes are reversible.

Since its first description >40 years ago, the neurological “critical period” has been predominantly described as an early, plastic postnatal brain development stage that rather abruptly advances to an aplastic or less plastic “adult” stage. Here, we show that chronic exposure of juvenile or adult rats to moderate-level acoustic noise results in a broad reversal of maturational changes that mark the infant-to-adult progression in the primary auditory cortex. In time, noise exposure reinstates critical period plasticity. Cortical changes resulting from noise exposure are again reversed to reestablish a physically and functionally normal adult cortex, by returning animals to natural acoustic environments. These studies show that at least some of neurological changes believed to mark the transition from the infantile to the mature (adult) stage are, by their nature, reversible.

Adult rats were trained to detect the occurrence of a two-element sound sequence in a background of nine other nontarget sound pairs. Training resulted in a modest, enduring, static expansion of the cortical areas of representation of both target stimulus sounds. More importantly, once the initial stimulus A in the target A-B sequence was presented, the cortical “map” changed dynamically, specifically to exaggerate further the representation of the “anticipated” stimulus B. If B occurred, it was represented over a larger cortical area by more strongly excited, more coordinated, and more selectively responding neurons. This biasing peaked at the expected time of B onset with respect to A onset. No dynamic biasing of responses was recorded for any sound presented in a nontarget pair. Responses to nontarget frequencies flanking the representation of B were reduced in area and in response strength only after the presentation of A at the expected time of B onset. This study shows that cortical areas are not representationally static but, to the contrary, can be biased moment by moment in time as a function of behavioral context.

Decision-making under risk entails the possibility of simultaneously receiving positive (reward) and negative (punishment) stimuli. To learn in this context, one must integrate conflicting information related to the magnitude of reward and the probability of punishment. Long-term inactivation of the basolateral amygdala (BLA) disrupts this process and increases risky behavior. In a recent study published in the Journal of Neuroscience , Orsini et al. (2017) showed that briefly inhibiting the BLA may result in increased or decreased risk-taking behavior, depending on the phase of the decision process in which BLA activity is disrupted. Here, we discuss the results and propose future experiments that could improve our understanding of how the BLA contributes to adaptive learning under risk and uncertainty. In complex, “real-world” environments, choices made may result in both rewards and adverse outcomes, each associated with different and often-changing probabilities. Decision-making under risk and uncertainty requires sustained attention and constant updating of learned rules to adequately valuate available alternatives. During risky decision-making, rewarding or punishing outcomes encountered following each decision facilitate learning through positive or negative reinforcement, respectively (Wachter et al., 2009). How individuals react to such competing environmental cues has been the focus of numerous studies in decision neuroscience (Preuschoff et al., 2015). These studies show that cultural, social, and genetic factors shape risk preference, although transient internal states, such as mood, fatigue, or recent experience, may also influence an individual’s propensity to risk-taking (Weber and Johnson, 2009). Located at the crossroads of corticolimbic circuits that mediate reinforcement learning, the basolateral amygdala (BLA) responds to arousing stimuli of both positive and negative valence (Shabel and Janak, 2009) and is necessary for the establishment of reward associations (Baxter and Murray, 2002) and fear conditioning (Krabbe et al., 2017). This functional heterogeneity …

Cognitive decline is a virtually universal aspect of the aging process. However, its neurophysiological basis remains poorly understood. We describe here more than 20 age-related cortical processing deficits in the primary auditory cortex of aging versus young rats that appear to be strongly contributed to by altered cortical inhibition. Consistent with these changes, we recorded in old rats a decrease in parvalbumin-labeled inhibitory cortical neurons. Furthermore, old rats were slower to master a simple behavior, with learning progressions marked by more false-positive responses. We then examined the effect of intensive auditory training on the primary auditory cortex in these aged rats by using an oddball discrimination task. Following training, we found a nearly complete reversal of the majority of previously observed functional and structural cortical impairments. These findings suggest that age-related cognitive decline is a tightly regulated plastic process, and demonstrate that most of these age-related changes are, by their fundamental nature, reversible.

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During early brain development and through 'adult' experience-dependent plasticity, neural circuits are shaped to represent the external world with high fidelity. When raised in a quiet environment, the rat primary auditory cortex (A1) has a well-defined 'critical period', lasting several days, for its representation of sound frequency. The addition of environmental noise extends the critical period duration as a variable function of noise level. It remains unclear whether critical period closure should be regarded as a unified, externally gated event that applies for all of A1 or if it is controlled by progressive, local, activity-driven changes in this cortical area. We found that rearing rats in the presence of a spectrally limited noise band resulted in the closure of the critical period for A1 sectors representing the noise-free spectral bands, whereas the critical period appeared to remain open in noise-exposed sectors, where the cortex was still functionally and physically immature.

Autism is a neurodevelopmental disorder clinically characterized by deficits in communication, lack of social interaction and, repetitive behaviors with restricted interests. A number of studies have reported that sensory perception abnormalities are common in autistic individuals and might contribute to the complex behavioral symptoms of the disorder. In this context, hearing incongruence is particularly prevalent. Considering that some of this abnormal processing might stem from the unbalance of inhibitory and excitatory drives in brain circuitries, we used an animal model of autism induced by valproic acid (VPA) during pregnancy in order to investigate the tonotopic organization of the primary auditory cortex (AI) and its local inhibitory circuitry. Our results show that VPA rats have distorted primary auditory maps with over-representation of high frequencies, broadly tuned receptive fields and higher sound intensity thresholds as compared to controls. However, we did not detect differences in the number of parvalbumin-positive interneurons in AI of VPA and control rats. Altogether our findings show that neurophysiological impairments of hearing perception in this autism model occur independently of alterations in the number of parvalbumin-expressing interneurons. These data support the notion that fine circuit alterations, rather than gross cellular modification, could lead to neurophysiological changes in the autistic brain.

The remarkable plastic nature of our brain, often manifesting itself via changes in how brain circuits code information, is at the origin of the many complex skills we master both during early development and adulthood. Intensive work in the last few decades in both human and animal models has revealed the multiple facets of brain plasticity and culminated recently in the explosion of the field of cognitive neurotherapeutics, bringing hope that brain plasticity can be used for the remediation of a wide range of cognitive, perceptual, or motor deficits. This growing interest in brain plasticity now shared by the general public has however shed light on the fact that our understanding of the regulating mechanisms of plasticity in the young, adult, and aging brain and how it can be best harnessed for therapeutic purposes remains poor. This limitation stands as a significant roadblock in the elaboration of effective science-based strategies for the remediation of neurological impairments at all ages and the preservation of optimal brain function in older adults. The objective of this special issue is to bring further attention to the field of neuroplasticity and cognitive neurotherapeutics by presenting novel original work performed in humans and animal models focusing on the impact of experience on brain circuits and behavior. Studying plasticity in sensory and motor systems is a particularly powerful means of understanding how brain circuits are shaped by experience. This is reflected in this issue which features several articles related to adaptive and maladaptive sensory or motor learning in various clinical populations. For example, M. M. Shiell et al. demonstrate that structural plasticity in a typical auditory cortical region, the right planum temporale, supports enhanced visual performance (motion detection) in deaf individuals, the first evidence of a neuroanatomical marker of crossmodal plasticity in this population. In the same vein, M. S. Houde et al. present an overview on the effects of deafness on body-related (nonvisual) processes, by reinterpreting the current literature on the altered processing as result of deafness from the “body” point of view. In their article, I. Riquelme et al. studied somatosensory processing in children with autism spectrum disorder. They evidenced using standardized tests that these individuals have predominantly abnormal processing of painful stimuli, implying a selective dysfunction of type C unmyelinated sensory fibers. These findings could provide a novel basis for the elaboration of sensory remediation strategies in this clinical population. P. Voss et al. examined the role of cholinergic system augmentation on auditory learning in young and older rats. Their results show that the speed and specificity of learning is significantly enhanced by the administration of rivastigmine in both young and older animals. Their findings also demonstrate that the rules of auditory cortical plasticity could be substantially different in the aging brain. Concerned with the mechanisms underlying auditory brainstem plasticity, H.-X. Mei et al. demonstrated that activity in the commissure of the inferior colliculus has a strong influence on the tuning properties of inferior collicular neurons. Their results could have important implications for the processing and integration of binaural interactions. The ability to shape “higher order” brain processes such as cognitive control with training is also now well recognized. In this issue, A. J. Wilkinson and L. Yang explore learning and benefits of inhibition tasks in older adults and find improvements with practice, though transfer to other cognitive abilities was limited to other tasks that shared a similar task structure. In this study, training was limited to 2 weeks and so the effects could potentially be enhanced through increased training dose or by pairing with neurostimulation. S. R. Schroeder et al. demonstrated in a study involving more than 200 young healthy participants that bilingualism and musicianship improve executive control and could therefore potentially be used in rehabilitations programs to boost cognitive performance. H. Takeuchi et al. show the utility of training on fast simple numerical calculations; one week of training enhanced processing speed and executive function in young adults. These effects were mediated by structural plasticity and perfusion related changes in frontopolar cortex. The development of noninvasive and safe techniques to augment brain plasticity such as transcranial direct current stimulation (tDCS) is very appealing for obvious reasons but their mechanisms of action and how to best use them are still not well established. Three studies presented in this special issue explored these questions. S. Sikstrom et al. examined whether tDCS would be more beneficial to individuals with low attentiveness compared to attentive people. Their results confirmed their hypotheses and strongly suggest that the benefits of tDCS likely interact with attentiveness. In another tDCS study, H. Kumru et al. investigated the use of mirror visual feedback (MVF) therapy as a tool to promote plastic brain changes and motor recovery. Their results show that a combination of motor training with MVF therapy may induce more robust neuroplastic changes through multisensory integration which is key for motor rehabilitation. Finally, G. Dumel et al. show that tDCS can significantly enhance motor learning in older adults raising the possibility that this technique could be useful to alleviate age-associated motor function decline. The enhancement of basic sensory processing or complex cognitive function requires the participation of a large number of complex molecules, many of which are still unknown or have poorly understood function. Hypothalamic neuropeptides are among those brain compounds that currently receive attention because of their powerful ability to shape neural circuits and behavior in both the developing and adult brains. J. Bakos et al. explored in this issue the role of several hypothalamic neuropeptides including oxytocin in the regulation of adult neurogenesis and neuritogenesis. This review highlights the potential role of these small molecules in a number of brain circuits linked to key social behaviors. In another article focusing on the molecular foundation of learning B. Gomez-Chacon et al. examined the impact of N-ethylmaleimide-sensitive factor expression on plasticity in the amygdala and perirhinal cortex. Their data provide new insight into some of the fundamental mechanisms involved in building taste recognition memory through sensory experience. M. Kruk-Slomka et al. demonstrated in mice that the endocannabinoid system played a significant role in the regulation of oxidative stress and long-term memory formation. Finally, in a thoughtful review article, K. M. Bieszczad and M. L. Phan explore the role of epigenetic mechanisms in the formation and regulation of memory encoding in sensory cortices. In summary, the articles contained in this issue highlight original findings obtained using a wide range of complementary techniques (fMRI, tDCS, single cell recordings, and pharmacology) in multiple brain systems and clinical populations that we believe will stimulate the continuing effort to better understand the relationship between brain plasticity, its regulators, and its impact on behavioral function. Etienne de Villers-Sidani Jyoti Mishra Xiaoming Zhou Patrice Voss

In both humans and rodents, decline in cognitive function is a hallmark of the aging process, the basis for this decrease has yet to be fully characterized. However, using aged rodent models, deficits in auditory processing have been associated with significant decreases in inhibitory signaling attributed to a loss of GABAergic interneurons. Not only are these interneurons crucial for pattern detection and other large-scale population dynamics, but they have also been linked to mechanisms mediating plasticity and learning, making them a prime candidate for study and modelling of modifications to cortical communication pathways in neurodegenerative diseases. Using the rat primary auditory cortex (A1) as a model, we probed the known markers of GABAergic interneurons with immunohistological methods, using antibodies against gamma aminobutyric acid (GABA), parvalbumin (PV), somatostatin (SOM), calretinin (CR), vasoactive intestinal peptide (VIP), choline acetyltransferase (ChAT), neuropeptide Y (NPY) and cholecystokinin (CCK) to document the changes observed in interneuron populations across the rat’s lifespan. This analysis provided strong evidence that several but not all GABAergic neurons were affected by the aging process, showing most dramatic changes in expression of parvalbumin (PV) and somatostatin (SOM) expression. With this evidence, we show how understanding these trajectories of cell counts may be factored into a simple model to quantify changes in inhibitory signalling across the course of life, which may be applied as a framework for creating more advanced simulations of interneuronal implication in normal cerebral processing, normal aging, or pathological processes.

In recent years, research on experience-dependent plasticity has provided valuable insight on adaptation to environmental input across the lifespan, and advances in understanding the minute cellular changes underlying the brain’s capacity for self-reorganization have opened exciting new possibilities for treating illness and injury. Ongoing work in this line of inquiry has also come to deeply influence another field: the cognitive neuroscience of the normal aging. This complex process, once dubbed as inevitable or beyond the reach of treatment, has been transformed into an arena of intense investigation and strategic intervention. However, important questions remain about this characterization of the aging brain, and the assumptions it makes about the social, cultural, and biological space occupied by cognition in the older individual and body. The following paper will provide a critical examination of the move from basic experiments on the neurophysiology of experience-dependent plasticity to the growing market for (and public conception of) cognitive aging as a medicalized space for intervention by neuroscience-backed technologies. Entangled with changing concepts of normality, pathology, and self-preservation, we will argue that this new understanding, led by personalized cognitive training strategies, is approaching a point where interdisciplinary research is crucial to provide a holistic and nuanced understanding of the aging process. This new outlook will allow us to move forward in a space where our knowledge, like our new conception of the brain, is never static.

Age-related impairments in the primary auditory cortex (A1) include poor tuning selectivity, neural desynchronization, and degraded responses to low-probability sounds. These changes have been largely attributed to reduced inhibition in the aged brain, and are thought to contribute to substantial hearing impairment in both humans and animals. Since many of these changes can be partially reversed with auditory training, it has been speculated that they might not be purely degenerative, but might rather represent negative plastic adjustments to noisy or distorted auditory signals reaching the brain. To test this hypothesis, we examined the impact of exposing young adult rats to 8 weeks of low-grade broadband noise on several aspects of A1 function and structure. We then characterized the same A1 elements in aging rats for comparison. We found that the impact of noise exposure on A1 tuning selectivity, temporal processing of auditory signal and responses to oddball tones was almost indistinguishable from the effect of natural aging. Moreover, noise exposure resulted in a reduction in the population of parvalbumin inhibitory interneurons and cortical myelin as previously documented in the aged group. Most of these changes reversed after returning the rats to a quiet environment. These results support the hypothesis that age-related changes in A1 have a strong activity-dependent component and indicate that the presence or absence of clear auditory input patterns might be a key factor in sustaining adult A1 function.

Age-related impairments in the primary auditory cortex (A1) include poor tuning selectivity, neural desynchronization and degraded responses to low-probability or "oddball" sounds. These changes have been for the most part attributed to reduced inhibition in the aged brain. Since many of these changes can be partially reversed with auditory training, it has been speculated that they might not be purely degenerative but might rather represent negative plastic adjustments to noisy or distorted auditory inputs. To test this hypothesis, we exposed young adult rats to low-grade broadband noise for 6 weeks and then compared the effect of this exposure on several aspects of A1 function and structure. We found that the impact of noise exposure on A1 tuning selectivity and responses to oddball tones was almost indistinguishable from the effect of natural aging. These changes were paralleled by alterations in A1 inhibitory interneuron populations in the exposed group. Moreover we found that noise exposure reduced the anatomical and functional connectivity of A1 to downstream cortical fields. These results support the hypothesis that age-related changes in cortical auditory pathways might have a strong activity-dependent component, making them potentially preventable and reversible.

Serotonin (5-HT) plays a key role in early brain development, and manipulation of 5-HT levels during this period can have lasting neurobiological and behavioral consequences. It is unclear how perinatal exposure to drugs, such as selective serotonin reuptake inhibitors (SSRIs), impacts cortical neural network function and what mechanism(s) may elicit the disruption of normal neuronal connections/interactions. In this article, we report on cortical wiring organization after pre- and postnatal exposure to the SSRI citalopram. We show that manipulation of 5-HT during early development in both in vitro and in vivo models disturbs characteristic chemoarchitectural and electrophysiological brain features, including changes in raphe and callosal connections, sensory processing, and myelin sheath formation. Also, drug-exposed rat pups exhibit neophobia and disrupted juvenile play behavior. These findings indicate that 5-HT homeostasis is required for proper brain maturation and that fetal/infant exposure to SSRIs should be examined in humans, particularly those with developmental dysfunction, such as autism.

The rodent auditory cortex has provided a particularly useful model for studying cortical plasticity phenomenology and mechanisms, both in infant and in adult animal models. Much of our initial understanding of the neurological processes underlying learning-induced changes in the cortex stems from the early exploitation of this model. More recent studies have provided a rich and elaborate demonstration of the "rules" governing representational plasticity induced during the critical period (CP) and in the longer post-CP "adult" plasticity epoch. These studies have also contributed importantly to the application of these "rules" to the development of practical training tools designed to improve the functional capacities of the auditory, language, and reading capacities of both children with developmental impairments and adults with acquired impairments in the auditory/aural speed and related cognitive domains. Using age as a connecting thread, we review recent studies performed in the rat primary auditory cortex (A1) that have provided further insight into the role of sensory experience in the shaping auditory signal representations, and into their possible role in shaping the machinery that regulates "adult" plasticity in A1. With this background, the role of auditory training in the remediation of auditory processing impairments is briefly discussed.

Perinatal asphyxia, a naturally and commonly occurring risk factor in birthing, represents one of the major causes of neonatal encephalopathy with long term consequences for infants. Here, degraded spectral and temporal responses to sounds were recorded from neurons in the primary auditory cortex (A1) of adult rats exposed to asphyxia at birth. Response onset latencies and durations were increased. Response amplitudes were reduced. Tuning curves were broader. Degraded successive-stimulus masking inhibitory mechanisms were associated with a reduced capability of neurons to follow higher-rate repetitive stimuli. The architecture of peripheral inner ear sensory epithelium was preserved, suggesting that recorded abnormalities can be of central origin. Some implications of these findings for the genesis of language perception deficits or for impaired language expression recorded in developmental disorders, such as autism spectrum disorders, contributed to by perinatal asphyxia, are discussed.

Experience-dependent plasticity during development results in the emergence of highly adapted representations of the external world in the adult brain. Previous studies have convincingly shown that the primary auditory cortex (A1)of the rat possesses a postnatal period of sensory input-driven plasticity but its precise timing ( onset, duration, end) has not been defined. In the present study, we examined the effects of pure-tone exposure on the auditory cortex of developing rat pups at different postnatal ages with a high temporal resolution. We found that pure-tone exposure resulted in profound, persistent alterations in sound representations in A1 only if the exposure occurred during a brief period extending from postnatal day 11 (P11) to P13. We also found that postnatal sound exposure in this epoch led to striking alterations in the cortical representation of sound intensity.