Showing papers in "Frontiers in Behavioral Neuroscience in 2013"
TL;DR: It is shown that music training in childhood is associated with reduced age-related decline of bimanual and unimanual motor skills in a MIDI keyboard motor learning task, indicating thatMusic training early in life may reduce age-associated decline of neural motor and cognitive networks.
Abstract: Aging is associated with deterioration of skilled manual movement. Specifically, aging corresponds with increased reaction time, greater movement duration, segmentation of movement, increased movement variability, and reduced ability to adapt to external forces and inhibit previously learned sequences. Moreover, it is thought that decreased lateralization of neural function in older adults may point to increased neural recruitment as a compensatory response to deterioration of key frontal and intra-hemispheric networks, particularly of callosal structures. However, factors that mediate age-related motor decline are not well understood. Here we show that music training in childhood is associated with reduced age-related decline of bimanual and unimanual motor skills in a MIDI keyboard motor learning task. Compared to older adults without music training, older adults with more than a year of music training demonstrated proficient bimanual and unimanual movement, evidenced by enhanced speed and decreased movement errors. Further, this group demonstrated significantly better implicit learning in the weather prediction task, a non-motor task. The performance of older adults with music training in those tasks was comparable to young adults. Older adults, however, displayed greater verbal ability compared to young adults irrespective of a past history of music training. Our results indicate that music training early in life may reduce age-associated decline of neural motor and cognitive networks.
357 citations
TL;DR: Stress-related disorders, such as depression and PTSD, are accompanied by glucocorticoid imbalances and structural/ functional alterations in limbic circuits that resemble those seen following chronic stress, suggesting that inappropriate processing of stressful information may be part of the pathological process.
Abstract: Stress initiates adaptive processes that allow the organism to physiologically cope with prolonged or intermittent exposure to real or perceived threats. A major component of this response is repeated activation of glucocorticoid secretion by the hypothalamo-pituitary-adrenocortical (HPA) axis, which promotes redistribution of energy in a wide range of organ systems, including the brain. Prolonged or cumulative increases in glucocorticoid secretion can reduce benefits afforded by enhanced stress reactivity and eventually become maladaptive. The long-term impact of stress is kept in check by the process of habituation, which reduces HPA axis responses upon repeated exposure to homotypic stressors and likely limits deleterious actions of prolonged glucocorticoid secretion. Habituation is regulated by limbic stress-regulatory sites, and is at least in part glucocorticoid feedback-dependent. Chronic stress also sensitizes reactivity to new stimuli. While sensitization may be important in maintaining response flexibility in response to new threats, it may also add to the cumulative impact of glucocorticoids on the brain and body. Finally, unpredictable or severe stress exposure may cause long-term and lasting dysregulation of the HPA axis, likely due to altered limbic control of stress effector pathways. Stress-related disorders, such as depression and PTSD, are accompanied by glucocorticoid imbalances and structural/ functional alterations in limbic circuits that resemble those seen following chronic stress, suggesting that inappropriate processing of stressful information may be part of the pathological process.
292 citations
TL;DR: The available evidence which converges to highlight the pivotal role of semantic memory in providing schemas and meaning whether one is engaged in autobiographical retrieval for the past, or indeed, is endeavoring to construct a plausible scenario of an event in the future is examined.
Abstract: Episodic memory refers to a complex and multifaceted process which enables the retrieval of richly detailed evocative memories from the past. In contrast, semantic memory is conceptualized as the retrieval of general conceptual knowledge divested of a specific spatiotemporal context. The neural substrates of the episodic and semantic memory systems have been dissociated in healthy individuals during functional imaging studies, and in clinical cohorts, leading to the prevailing view that episodic and semantic memory represent functionally distinct systems subtended by discrete neurobiological substrates. Importantly, however, converging evidence focusing on widespread neural networks now points to significant overlap between those regions essential for retrieval of autobiographical memories, episodic learning, and semantic processing. Here we review recent advances in episodic memory research focusing on neurodegenerative populations which has proved revelatory for our understanding of the complex interplay between episodic and semantic memory. Whereas episodic memory research has traditionally focused on retrieval of autobiographical events from the past, we also include evidence from the recent paradigm shift in which episodic memory is viewed as an adaptive and constructive process which facilitates the imagining of possible events in the future. We examine the available evidence which converges to highlight the pivotal role of semantic memory in providing schemas and meaning whether one is engaged in autobiographical retrieval for the past, or indeed, is endeavoring to construct a plausible scenario of an event in the future. It therefore seems plausible to contend that semantic processing may underlie most, if not all, forms of episodic memory, irrespective of temporal condition.
267 citations
TL;DR: This review focuses on the interaction of orexin neurons with emotion, reward, and energy homeostasis systems, and how these connectivities are likely to be highly important to maintain proper vigilance states.
Abstract: Orexin deficiency results in narcolepsy in humans, dogs, and rodents, suggesting that the orexin system is particularly important for maintenance of wakefulness. However, orexin neurons are ‘multi-tasking’ neurons that regulate sleep/wake states as well as feeding behavior, emotion, and reward processes. Orexin deficiency causes abnormalities in energy homeostasis, stress-related behavior, and reward systems. Orexin excites waking-active monoaminergic and cholinergic neurons in the hypothalamus and brain stem regions to maintain a long, consolidated waking period. Orexin neurons also have reciprocal links with the hypothalamic nucleus, which regulates feeding. Moreover, the responsiveness of orexin neurons to peripheral metabolic cues suggests that these neurons have an important role as a link between energy homeostasis and vigilance states. The link between orexin and the ventral tegmental nucleus serves to motivate an animal to engage in goal-directed behavior. This review focuses on the interaction of orexin neurons with emotion, reward, and energy homeostasis systems. These connectivities are likely to be highly important to maintain proper vigilance states.
214 citations
TL;DR: It is argued that, to measure age differential effects of prior knowledge on memory, it is necessary to distinguish the availability of priorknowledge from its accessibility and use and postulate how these may be related to the development of the use ofPrior knowledge for remembering.
Abstract: Across ontogenetic development, individuals gather manifold experiences during which they detect regularities in their environment and thereby accumulate knowledge. This knowledge is used to guide behavior, make predictions, and acquire further new knowledge. In this review, we discuss the influence of prior knowledge on memory from both the psychology and the emerging cognitive neuroscience literature and provide a developmental perspective on this topic. Recent neuroscience findings point to a prominent role of the medial prefrontal cortex (mPFC) and of the hippocampus (HC) in the emergence of prior knowledge and in its application during the processes of successful memory encoding, consolidation, and retrieval. We take the lateral PFC into consideration as well and discuss changes in both medial and lateral PFC and HC across development and postulate how these may be related to the development of the use of prior knowledge for remembering. For future direction, we argue that, to measure age differential effects of prior knowledge on memory, it is necessary to distinguish the availability of prior knowledge from its accessibility and use.
187 citations
TL;DR: Transgenic mice in which mHb cells were selectively ablated postnatally played a crucial role in inhibitory control and cognition-dependent executive functions and exhibited abnormalities in a wide range of behavioral domains are generated.
Abstract: The habenular complex linking forebrain and midbrain structures is subdivided into the medial (mHb) and the lateral nuclei (lHb). The mHb is characterized by the expression of specific nicotinic acetylcholine receptor isoforms and the release of acetylcholine to the interpeduncular nucleus (IPN), the sole output region of the mHb. The specific function of this circuit, however, is poorly understood. Here we generated transgenic mice in which mHb cells were selectively ablated postnatally. These lesions led to large reductions in acetylcholine levels within the IPN. The mutant mice exhibited abnormalities in a wide range of behavioral domains. They tended to be hyperactive during the early night period and were maladapted when repeatedly exposed to new environments. Mutant mice also showed a high rate of premature responses in the 5-choice serial reaction time task (5CSRTT), indicating impulsive and compulsive behavior. Additionally, mice also exhibited delay and effort aversion in a decision-making test, deficits in spatial memory, a subtle increase in anxiety levels, and attenuated sensorimotor gating. IntelliCage studies under social housing conditions confirmed hyperactivity, environmental maladaptation, and impulsive/compulsive behavior, delay discounting, deficits in long-term spatial memory, and reduced flexibility in complex learning paradigms. In 5CSRTT and adaptation tasks, systemic administration of nicotine slowed down a nose-poke reaction and enhanced adaptation in control but not mutant mice. These findings demonstrate that the mHb–IPN pathway plays a crucial role in inhibitory control and cognition-dependent executive functions.
154 citations
TL;DR: OT’s effects reach beyond maternal attachment and pair bonds to play a role in affiliative behavior underlying “friendships”, organization of broad social structures, and maintenance of established social relationships with individuals or groups.
Abstract: In recent decades, scientific understanding of the many roles of oxytocin in social behavior has advanced tremendously. The focus of this research has been on maternal attachments and reproductive pair-bonds, and much less is known about the substrates of sociality outside of reproductive contexts. It is now apparent that oxytocin influences many aspects of social behavior including recognition, trust, empathy, and other components of the behavioral repertoire of social species. This review provides a comparative perspective on the contributions of oxytocin to life in mammalian social groups. We provide background on the functions of oxytocin in maternal attachments and the early social environment, and give an overview of the role of oxytocin circuitry in support of different mating systems. We then introduce peer relationships in group-living rodents as a means for studying the importance of oxytocin in non-reproductive affiliative behaviors. We review species differences in oxytocin receptor distributions in solitary and group-living species of South American tuco-tucos and in African mole-rats, as well as singing mice. We discuss variation in oxytocin receptor levels with seasonal changes in social behavior in female meadow voles, and the effects of oxytocin manipulations on peer huddling behavior. Finally, we discuss avenues of promise for future investigation, and relate current findings to research in humans and non-human primates. There is growing evidence that oxytocin is involved in social selectivity, including increases in aggression toward social outgroups and decreased huddling with unfamiliar individuals, which may support existing social structures or relationships at the expense of others. Oxytocin’s effects reach beyond maternal attachment and pair bonds to play a role in affiliative behavior underlying “friendships,” organization of broad social structures, and maintenance of established social relationships with individuals or groups.
153 citations
TL;DR: An hypothesis is proposed that aims to solve the problem of how motivational value is assigned to goals on the basis of internal states and environmental stimuli, and how this supports goal selection processes and has the potential to integrate existing interpretations of motivational value and goal selection.
Abstract: Goal-directed behavior is a fundamental means by which animals can flexibly solve the challenges posed by variable external and internal conditions. Recently, the processes and brain mechanisms underlying such behavior have been extensively studied from behavioral, neuroscientific and computational perspectives. This research has highlighted the processes underlying goal-directed behavior and associated brain systems including prefrontal cortex, basal ganglia and, in particular therein, the nucleus accumbens (NAcc). This paper focusses on one particular process at the core of goal-directed behavior: how motivational value is assigned to goals on the basis of internal states and environmental stimuli, and how this supports goal selection processes. Various biological and computational accounts have been given of this problem and of related multiple neural and behavior phenomena, but we still lack an integrated hypothesis on the generation and use of value for goal selection. This paper proposes an hypothesis that aims to solve this problem and is based on this key elements: (a) amygdala and hippocampus establish the motivational value of stimuli and goals; (b) prefrontal cortex encodes various types of action outcomes; (c) NAcc integrates different sources of value, representing them in terms of a common currency with the aid of dopamine, and thereby plays a major role in selecting action outcomes within prefrontal cortex. The “goals” pursued by the organism are the outcomes selected by these processes. The hypothesis is developed in the context of a critical review of relevant biological and computational literature which offer it support. The paper shows how the hypothesis has the potential to integrate existing interpretations of motivational value and goal selection.
139 citations
TL;DR: An overview of neuroimaging findings related to resilience is provided, which points at brain circuitries involved in stress and emotion regulation, with more efficient processing and regulation associated with resilience.
Abstract: There is a high degree of intra-individual variation in how individuals respond to stress. This becomes evident when exploring the development of posttraumatic symptoms or stress-related disorders after exposure to trauma. Whether or not an individual develops posttraumatic symptoms after experiencing a traumatic event is partly dependent on a person’s resilience. Resilience can be broadly defined as the dynamic process encompassing positive adaptation within the context of significant adversity. Even though research into the neurobiological basis of resilience is still in its early stages, these insights can have important implications for the prevention and treatment of stress-related disorders. Neuroimaging studies contribute to our knowledge of intra-individual variability in resilience and the development of posttraumatic symptoms or other stress-related disorders. This review provides an overview of neuroimaging findings related to resilience. Structural, resting-state and task-related neuroimaging results associated with resilience are discussed. There are a limited number of studies available and neuroimaging research of resilience is still in its infancy. The available studies point at brain circuitries involved in stress and emotion regulation, with more efficient processing and regulation associated with resilience.
137 citations
TL;DR: Overall, these PD models are suitable for mimicking the motor symptoms associated to PD, with each encompassing other relevant NMS components of the disorder that may prove beneficial for further studies in PD.
Abstract: Parkinson's disease (PD) is classically characterized by motor symptoms; however, non-motor manifestations are increasingly recognized as relevant in this condition. Given the influence of these non-motor symptoms in the well-being of PD patients, it is of major interest to assess these features in studies using PD animal models. Therefore, the present study aims to compare the motor, emotional and cognitive behaviour of three animal models of PD: i) the 6-hydroxydopamine (6-OHDA) lesion model; ii) the paraquat (PQ) induced model and iii) a genetic model based on α-synuclein overexpression (α-syn). 6-OHDA and α-syn vector were injected bilaterally in the substantia nigra of adult male Wistar rats; as for PQ delivery, micro-osmotic pumps were implanted in the interscapular region. Motor deficits were observed in all models. In addition to the motor impairments, the animals of α-syn model presented also a reduction of exploratory activity. Animals exposed to 6-OHDA and PQ displayed a significant increase in both anxiety and depressive-like behavior. Interestingly, only in the 6-OHDA model there was an impairment in working memory performance. Overall, these PD models are suitable for mimicking the motor symptoms associated to PD, and some of them encompass other relevant components of the disorder.
133 citations
TL;DR: The data establish that the full-body illusion (FBI) alters bodily self-consciousness and instigates widespread physiological changes in the participant's body.
Abstract: A central feature of our consciousness is the experience of the self as a unified entity residing in a physical body, termed bodily self-consciousness. This phenomenon includes aspects such as the sense of owning a body (also known as body ownership) and has been suggested to arise from the integration of sensory signals from the body. Several studies have shown that temporally synchronous tactile stimulation of the real body and visual stimulation of a fake or virtual body can induce changes in bodily self-consciousness, typically resulting in a sense of illusory ownership over the fake body. The present study assessed the effect of anatomical congruency of visuo-tactile stimulation on bodily self-consciousness. A virtual body was presented and temporally synchronous visuo-tactile stroking was applied simultaneously to the participants' body and to the virtual body. We manipulated the anatomical locations of the visuo-tactile stroking (i.e., on the back, on the leg), resulting in congruent stroking (stroking was felt and seen on the back or the leg) or incongruent stroking (i.e., stroking was felt on the leg and seen on the back). We measured self-identification with the virtual body and self-location as well as skin temperature. Illusory self-identification with the avatar as well as changes in self-location were experienced in the congruent stroking conditions. Participants showed a decrease in skin temperature across several body locations during congruent stimulation. These data establish that the full-body illusion (FBI) alters bodily self-consciousness and instigates widespread physiological changes in the participant's body.
TL;DR: It is demonstrated that the BLA projection either directly into the NAc, or indirectly via the PL, is a necessary regulator of drug-seeking behavior.
Abstract: Stimuli previously associated with drugs of abuse can become triggers that elicit craving and lead to drug-seeking behavior. The basolateral amygdala (BLA) is a key neural structure involved in cue-induced reinstatement of cocaine seeking. Previous studies have also implicated projections from the BLA directly to the nucleus accumbens (NAc) in these behaviors. However, other structures critically involved in cocaine seeking are targets of BLA innervation, including the prelimbic prefrontal cortex (PL). It has been shown that BLA or PL innervation direct to the NAc can modulate reward-related behaviors but the BLA also projects to the PL, and given the importance of the PL projection to the NAc for reinstated drug seeking, we hypothesized the BLA to PL projection may indirectly influence behavior via PL innervation to the NAc. We delivered a virus expressing the inhibitory optogenetic construct ArchT into the BLA and implanted fiber optics above the injection site or axon terminal fields in either the NAc or PL. Rats then went through 12 days of cocaine self-administration followed by extinction training. Following extinction, animals underwent cue-induced reinstatement sessions in the presence or absence of optical inhibition. Inactivation of the BLA and either the BLA core subcompartment of the NAc (BLA-to-NAcore) BLA-to-PL projections inhibited cue-induced reinstatement. These data demonstrate that the BLA projection either directly into the NAc, or indirectly via the PL, is a necessary regulator of drug-seeking behavior.
TL;DR: In two Pavlovian fear-conditioning experiments, it is shown that gradually reducing the frequency of aversive stimuli, rather than eliminating them abruptly, prevents the recovery of fear.
Abstract: Fear memories are notoriously difficult to erase, often recovering over time. The longstanding explanation for this finding is that, in extinction training, a new memory is formed that competes with the old one for expression but does not otherwise modify it. This explanation is at odds with traditional models of learning such as Rescorla-Wagner and reinforcement learning. A possible reconciliation that was recently suggested is that extinction training leads to the inference of a new state that is different from the state that was in effect in the original training. This solution, however, raises a new question: under what conditions are new states, or new memories formed? Theoretical accounts implicate persistent large prediction errors in this process. As a test of this idea, we reasoned that careful design of the reinforcement schedule during extinction training could reduce these prediction errors enough to prevent the formation of a new memory, while still decreasing reinforcement sufficiently to drive modification of the old fear memory. In two Pavlovian fear-conditioning experiments, we show that gradually reducing the frequency of aversive stimuli, rather than eliminating them abruptly, prevents the recovery of fear. This finding has important implications for theories of state discovery in reinforcement learning.
TL;DR: Quantitative mapping of selective OXTR ligand binding during postnatal development in the mouse reveals an unexpected, transient expression in layers II/III throughout the mouse neocortex.
Abstract: Oxytocin (OXT) has drawn increasing attention as a developmentally relevant neuropeptide given its role in the brain regulation of social behavior. It has been suggested that OXT plays an important role in the infant brain during caregiver attachment in nurturing familial contexts, but there is incomplete experimental evidence. Mouse models of OXT system genes have been particularly informative for the role of the OXT system in social behavior, however, the developing brain areas that could respond to ligand activation of the OXT receptor (OXTR) have yet to be identified in this species. Here we report new data revealing dynamic ligand-binding distribution of OXTR in the developing mouse brain. Using male and female C57BL/6J mice at postnatal days (P) 0, 7, 14, 21, 35, and 60 we quantified OXTR ligand binding in several brain areas which changed across development. Further, we describe OXTR ligand binding in select tissues of the near-term whole embryo at E18.5. Together, these data aid in the interpretation of findings in mouse models of the OXT system and generate new testable hypotheses for developmental roles for OXT in mammalian systems. We discuss our findings in the context of developmental disorders (including autism), attachment biology, and infant physiological regulation.
TL;DR: The results demonstrate the effectiveness of a novel viral targeting strategy that can be used to restrict opsin expression to dopamine cells in standard outbred animals and provide the first causal evidence demonstrating that tonic activation of VTA dopamine neurons selectively decreases ethanol self-administration behaviors.
Abstract: There is compelling evidence that acute ethanol exposure stimulates ventral tegmental area (VTA) dopamine cell activity and that VTA-dependent dopamine release in terminal fields within the nucleus accumbens plays an integral role in the regulation of ethanol drinking behaviors Unfortunately, due to technical limitations, the specific temporal dynamics linking VTA dopamine cell activation and ethanol self-administration are not known In fact, establishing a causal link between specific patterns of dopamine transmission and ethanol drinking behaviors has proven elusive Here, we sought to address these gaps in our knowledge using a newly developed viral-mediated gene delivery strategy to selectively express Channelrhodopsin-2 (ChR2) on dopamine cells in the VTA of wild-type rats We then used this approach to precisely control VTA dopamine transmission during voluntary ethanol drinking sessions The results confirmed that ChR2 was selectively expressed on VTA dopamine cells and delivery of blue light pulses to the VTA induced dopamine release in accumbal terminal fields with very high temporal and spatial precision Brief high frequency VTA stimulation induced phasic patterns of dopamine release in the nucleus accumbens Lower frequency stimulation, applied for longer periods mimicked tonic increases in accumbal dopamine Notably, using this optogenetic approach in rats engaged in an intermittent ethanol drinking procedure, we found that tonic, but not phasic, stimulation of VTA dopamine cells selectively attenuated ethanol drinking behaviors Collectively, these data demonstrate the effectiveness of a novel viral targeting strategy that can be used to restrict opsin expression to dopamine cells in standard outbred animals and provide the first causal evidence demonstrating that tonic activation of VTA dopamine neurons selectively decreases ethanol self-administration behaviors
TL;DR: To accurately assess the large influx of papers purporting to attribute pattern separation to the DG, the concept must be reassessed; the original definition of pattern separation as a computational process and its newer, colloquial definition as a form of behavioral context discrimination must be accurately parsed if relations between the data are to be made.
Abstract: The dentate gyrus (DG) is postulated to be a “pattern separator” (Marr, 1971; Rolls, 1989a,b, 1990; Treves and Rolls, 1994). Yet, the definition of pattern separation has become a haze, with researchers using the term interchangeably to describe computational processes, changes in cell ensemble activity, and even behavioral phenomena (Leutgeb et al., 2007; McHugh et al., 2007; Clelland et al., 2009; Bakker et al., 2010). To accurately assess the large influx of papers purporting to attribute pattern separation to the DG, the concept must be reassessed; the original definition of pattern separation as a computational process and its newer, colloquial definition as a form of behavioral context discrimination must be accurately parsed if relations between the data are to be made.
TL;DR: Observations of the general health of Wistar dams treated with a single intraperitoneal injection of 500 or, 600 mg/kg VPA on embryonic day E12.5 are presented and further documentation of developmental health may guide sub-grouping of individuals in a way to better predict core symptom severity.
Abstract: Autism is a neurodevelopmental condition diagnosed by impaired social interaction, abnormal communication and, stereotyped behaviors. While post-mortem and imaging studies have provided good insights into the neurobiological symptomology of autism, animal models can be used to study the neuroanatomical, neurophysiological and molecular mediators in more detail and in a more controlled environment. The valproic acid (VPA) rat model is an environmentally triggered model with strong construct and clinical validity. It is based on VPA teratogenicity in humans, where mothers who are medicated with VPA during early pregnancy show an increased risk for giving birth to an autistic child. In rats, early embryonic exposure, around the time of neural tube closure, leads to autism-like anatomical and behavioral abnormalities in the offspring. Considering the increasing use of the VPA rat model, we present our observations of the general health of Wistar dams treated with a single intraperitoneal injection of 500 or, 600 mg/kg VPA on embryonic day E12.5, as well as their male and female offspring, in comparison to saline-exposed controls. We report increased rates of complete fetal reabsorption after both VPA doses. VPA 500 mg/kg showed no effect on dam body weight during pregnancy or, on litter size. Offspring exposed to VPA 500 mg/kg showed smaller brain mass on postnatal days 1 (P1) and 14 (P14), in addition to abnormal nest seeking behavior at P10 in the olfactory discrimination test, relative to controls. We also report increased rates of physical malformations in the offspring, rare occurrences of chromodacryorrhea and, developmentally similar body mass gain. Further documentation of developmental health may guide sub-grouping of individuals in a way to better predict core symptom severity.
TL;DR: It is found that individuals with the Met/Met genotype demonstrated higher fear-potentiated startle to the CS− (safety signal) and during extinction of the CS+ (danger signal) compared to Val/Met and Val/Val genotypes, and multiple differential mechanisms for regulating COMT function are associated with impaired fear inhibition in PTSD.
Abstract: The catechol-O-methyltransferase (COMT) enzyme is critical for the catabolic regulation of synaptic dopamine, resulting in altered cortical functioning. The COMT Val158Met polymorphism has been implicated in human mental illness, with Met/Met homozygotes associated with increased susceptibility to posttraumatic stress disorder (PTSD). Our primary objective was to examine the intermediate phenotype of fear inhibition in PTSD stratified by COMT genotype (Met/Met, Val/Met, and Val/Val) and differential gene regulation via methylation status at CpG sites in the COMT promoter region. More specifically, we examined the potential interaction of COMT genotype and PTSD diagnosis on fear-potentiated startle during fear conditioning and extinction and COMT DNA methylation levels (as determined using genomic DNA isolated from whole blood) . Participants were recruited from medical and gynecological clinics of an urban hospital in Atlanta, Georgia. We found that individuals with the Met/Met genotype demonstrated higher fear-potentiated startle to the CS- (safety signal) and during extinction of the CS+ (danger signal) compared to Val/Met and Val/Val genotypes. The PTSD+ Met/Met genotype group had the greatest impairment in fear inhibition to the CS- (p=.006), compared to Val carriers. In addition, the Met/Met genotype was associated with DNA methylation at 4 CpG sites, 2 of which were associated with impaired fear inhibition to the safety signal. These results suggest that multiple differential mechanisms for regulating COMT function – at the level of protein structure via the Val158Met genotype and at the level of gene regulation via differential methylation - are associated with impaired fear inhibition in PTSD.
TL;DR: The progress made in defining behavioral criteria of episodic-like memory in animals (and humans) as well as the perspectives in developing novel tests of human episodic memory which can also account for phenomenological aspects of episodi memory such as autonoetic awareness are summarized.
Abstract: Episodic memory refers to the conscious recollection of a personal experience that contains information on what has happened and also where and when it happened. Recollection from episodic memory also implies a kind of first-person subjectivity that has been termed autonoetic consciousness. Episodic memory is extremely sensitive to cerebral aging and neurodegenerative diseases. In Alzheimer’s disease deficits in episodic memory function are among the first cognitive symptoms observed. Furthermore, impaired episodic memory function is also observed in a variety of other neuropsychiatric diseases including dissociative disorders, schizophrenia, and Parkinson disease. Unfortunately, it is quite difficult to induce and measure episodic memories in the laboratory and it is even more difficult to measure it in clinical populations. Presently, the tests used to assess episodic memory function do not comply with even down-sized definitions of episodic-like memory as a memory for what happened, where, and when. They also require sophisticated verbal competences and are difficult to apply to patient populations. In this review, we will summarize the progress made in defining behavioral criteria of episodic-like memory in animals (and humans) as well as the perspectives in developing novel tests of human episodic memory which can also account for phenomenological aspects of episodic memory such as autonoetic awareness. We will also define basic behavioral, procedural, and phenomenological criteria which might be helpful for the development of a valid and reliable clinical test of human episodic memory.
TL;DR: This paper suggests that (1) the core features assumed unique to episodic memory are shared by semantic memory, and (2) episodi memory cannot be fully understood unless one appreciates that episodic recollection requires the coordinated function of a number of distinct, yet interacting, “enabling” systems.
Abstract: Episodic memory often is conceptualized as a uniquely human system of long-term memory that makes available knowledge accompanied by the temporal and spatial context in which that knowledge was acquired. Retrieval from episodic memory entails a form of first–person subjectivity called autonoetic consciousness that provides a sense that a recollection was something that took place in the experiencer’s personal past. In this paper I expand on this definition of episodic memory. Specifically, I suggest that (a) the core features assumed unique to episodic memory are shared by semantic memory, (b) episodic memory cannot be fully understood unless one appreciates that episodic recollection requires the coordinated function of a number of distinct, yet interacting, “enabling” systems. Although these systems – ownership, self, subjective temporality, and agency – are not traditionally viewed as memorial in nature, each is necessary for episodic recollection and jointly they may be sufficient, and (c) the type of subjective awareness provided by episodic recollection (autonoetic) is relational rather than intrinsic – i.e., it can be lost in certain patient populations, thus rendering episodic memory content indistinguishable from the content of semantic long-term memory.
TL;DR: As robot and human touch are highly comparable in terms of perceived pleasantness, handheld stimulation may be used in studies of touch hedonia where robot stimulation is not applicable (for instance in children or certain body parts).
Abstract: Introduction. The aim of our study was to investigate whether a pleasant tactile stimulation which is manually produced is qualitatively comparable to an analogous tactile stimulation produced instead by a mechanical source. Methods. 31 subjects (16 men, 15 women, mean age 24.5+/-2.6 years) were tested under four different conditions in a repeated measurements design. A pleasant caress-like brush stroke on the hairy skin of the forearm was either produced by a robot or by hand with three different velocities (0.3 cm/s, 3 cm/s and 30 cm/s). In two conditions the subjects were informed about the stroke´s source, whereas in two different conditions they were not. Subsequent to the stimulation, the subjects were asked to rate both pleasantness and intensity of each tactile sensation. Results. Consistently, pleasantness ratings were very similar in both conditions. This was found across stimulus velocities and regardless of whether the subjects were informed about the source of the on-going stroke or not. In contrast, intensity ratings were significantly higher in the handheld condition for the two slower velocities, but not for the fastest one. Conclusion. As robot and human touch are highly comparable in terms of perceived pleasantness, handheld stimulation may be used in studies of touch hedonia where robot stimulation is not applicable (for instance in children or certain body parts).
TL;DR: Differences between psychosensory PD responses in alerting, orienting, and executive conflict monitoring tasks are explored to generate estimates of concurrent locus coeruleus (LC) noradrenergic input trajectories in healthy human adults using the attention networks test (ANT).
Abstract: Attention capacities, alerting responses, orienting to sensory stimulation, and executive monitoring of performance are considered independent yet interrelated systems. These operations play integral roles in regulating the behavior of diverse species along the evolutionary ladder. Each of the primary attention constructs—alerting, orienting, and executive monitoring—involves salient autonomic correlates as evidenced by changes in reactive pupil dilation (PD), heart rate, and skin conductance. Recent technological advances that use remote high-resolution recording may allow the discernment of temporo-spatial attributes of autonomic responses that characterize the alerting, orienting, and executive monitoring networks during free viewing, irrespective of voluntary performance. This may deepen the understanding of the roles of autonomic regulation in these mental operations and may deepen our understanding of behavioral changes in verbal as well as in non-verbal species. The aim of this study was to explore differences between psychosensory PD responses in alerting, orienting, and executive conflict monitoring tasks to generate estimates of concurrent locus coeruleus (LC) noradrenergic input trajectories in healthy human adults using the attention networks test (ANT). The analysis revealed a construct-specific pattern of pupil responses: alerting is characterized by an early component (Pa), its acceleration enables covert orienting, and executive control is evidenced by a prominent late component (Pe). PD characteristics seem to be task-sensitive, allowing exploration of mental operations irrespective of conscious voluntary responses. These data may facilitate development of studies designed to assess mental operations in diverse species using autonomic responses.
TL;DR: This work argues that this dissociation may be too simplistic, and a continuum model may be better suited to address the role of the hippocampus in retrieval of remote memories, and presents the Competitive Trace Theory, a novel candidate model that may provide some resolution to the memory consolidation debate.
Abstract: Much controversy exists regarding the role of the hippocampus in retrieval. The two dominant and competing accounts have been the Standard Model of Systems Consolidation (SMSC) and Multiple Trace Theory (MTT), which specifically make opposing predictions as to the necessity of the hippocampus for retrieval of remote memories. Under SMSC, memories eventually become independent of the hippocampus as they become more reliant on cortical connectivity, and thus the hippocampus is not required for retrieval of remote memories, only recent ones. MTT on the other hand claims that the hippocampus is always required no matter the age of the memory. We argue that this dissociation may be too simplistic, and a continuum model may be better suited to address the role of the hippocampus in retrieval of remote memories. Such a model is presented here with the main function of the hippocampus during retrieval being “recontextualization,” or the reconstruction of memory using overlapping traces. As memories get older, they are decontextualized due to competition among partially overlapping traces and become more semantic and reliant on neocortical storage. In this framework dubbed the Competitive Trace Theory (CTT), consolidation events that lead to the strengthening of memories enhance conceptual knowledge (semantic memory) at the expense of contextual details (episodic memory). As a result, remote memories are more likely to have a stronger semantic representation. At the same time, remote memories are also more likely to include illusory details. The CTT is a novel candidate model that may provide some resolution to the memory consolidation debate.
TL;DR: It is demonstrated for the first time that fear conditioning transiently modifies a proteasome regulatory subunit and proteasomesome catalytic activity in the mammalian brain in a CaMKII-dependent manner, indicating a novel role for Ca MKII in memory formation through its regulation of protein degradation and suggesting that CaMK II regulates Rpt6 phosphorylation and prote asome function both in vitro and in vivo.
Abstract: CaMKII and Protein Kinase A (PKA) are thought to be critical for synaptic plasticity and memory formation through their regulation of protein synthesis. Consistent with this, numerous studies have reported that CaMKII, PKA and protein synthesis are critical for long-term memory formation. Recently, we found that protein degradation through the ubiquitin-proteasome system is also critical for long-term memory formation in the amygdala. However, the mechanism by which ubiquitin-proteasome activity is regulated during memory formation and how protein degradation interacts with known intracellular signaling pathways important for learning remain unknown. Recently, evidence has emerged suggesting that both CaMKII and PKA are capable of regulating proteasome activity in vitro through the phosphorylation of proteasome regulatory subunit Rpt6 at Serine-120, though whether they regulate Rpt6 phosphorylation and proteasome function in vivo remains unknown. In the present study we demonstrate for the first time that fear conditioning transiently modifies a proteasome regulatory subunit and proteasome catalytic activity in the mammalian brain in a CaMKII-dependent manner. We found increases in the phosphorylation of proteasome ATPase subunit Rpt6 at Serine-120 and an enhancement in proteasome activity in the amygdala following fear conditioning. Pharmacological manipulation of CaMKII, but not PKA, in vivo significantly reduced both the learning-induced increase in Rpt6 Serine-120 phosphorylation and the increase in proteasome activity without directly affecting protein polyubiquitination levels. These results indicate a novel role for CaMKII in memory formation through its regulation of protein degradation and suggest that CaMKII regulates Rpt6 phosphorylation and proteasome function both in vitro and in vivo.
TL;DR: It is suggested that environmental stressors such as social isolation render parvalbumin-positive interneurons (PVIs) vulnerable to oxidative stress, and the down-regulation of PGC-1α, a master regulator of mitochondrial energy metabolism and anti-oxidant defense, following the deletion of NMDARs is proposed.
Abstract: Schizophrenia etiology is thought to involve an interaction between genetic and environmental factors during postnatal brain development. However, there is a fundamental gap in our understanding of the molecular mechanisms by which environmental factors interact with genetic susceptibility to trigger symptom onset and disease progression. In this review, we summarize the most recent findings implicating oxidative stress as one mechanism by which environmental insults, especially early life social stress, impact the development of schizophrenia. Based on a review of the literature and the results of our own animal model, we suggest that environmental stressors such as social isolation render parvalbumin-positive interneurons vulnerable to oxidative stress. We previously reported that social isolation stress exacerbates many of the schizophrenia-like phenotypes seen in a conditional genetic mouse model of schizophrenia in which NMDARs are selectively ablated in half of cortical and hippocampal interneurons during early postnatal development (Belforte et al., 2010). We have since revealed that this social isolation-induced effect is caused by impairments in the antioxidant defense capacity in the parvalbumin-positive interneurons in which NMDARs are ablated. We propose that this effect is mediated by the down-regulation of PGC-1α, a master regulator of mitochondrial energy metabolism and anti-oxidant defense, following the deletion of NMDARs (Jiang et al, 2013). Other potential molecular mechanisms underlying redox dysfunction upon gene and environmental interaction will be discussed, with a focus on the unique properties of parvalbumin-positive interneurons.
TL;DR: Whether principles derived from the aversive literature are applicable to appetitive settings, and also whether the expanding literature in appetitive paradigms is informative for fear memory reconsolidation are focused on.
Abstract: Memory reconsolidation has been observed across species and in a number of behavioral paradigms. The majority of memory reconsolidation studies have been carried out in Pavlovian fear conditioning and other aversive memory settings, with potential implications for the treatment of post-traumatic stress disorder. However, there is a growing literature on memory reconsolidation in appetitive reward-related memory paradigms, including translational models of drug addiction. While there appears to be substantial similarity in the basic phenomenon and underlying mechanisms of memory reconsolidation across unconditioned stimulus valence, there are also notable discrepancies. These arise both when comparing aversive to appetitive paradigms and also across different paradigms within the same valence of memory. We review the demonstration of memory reconsolidation across different aversive and appetitive memory paradigms, the commonalities and differences in underlying mechanisms and the conditions under which each memory undergoes reconsolidation. We focus particularly on whether principles derived from the aversive literature are applicable to appetitive settings, and also whether the expanding literature in appetitive paradigms is informative for fear memory reconsolidation.
TL;DR: Pathological gambling is characterized by maladaptive patterns of gambling that are associated with significant impairments in functioning and prompted the reclassification of PG in DSM-5 as an addictive disorder.
Abstract: Pathological gambling [PG—now termed “gambling disorder” in DSM-5 (APA, 2013; Petry et al., 2013)] is characterized by maladaptive patterns of gambling that are associated with significant impairments in functioning. Over the past decade, significant advances have been made in understanding the pathophysiology of PG (Potenza, 2013). Similarities between PG and substance-use disorders (Petry, 2006; Potenza, 2006; Leeman and Potenza, 2012) prompted the reclassification of PG in DSM-5 as an addictive disorder (rather than an impulse-control disorder, as was the case in DSM-IV).
TL;DR: The data indicate that beyond their role in the control of circadian rhythm, cryptochrome genes have a direct influence in cognitive function, anxiety-related behaviors and sensitivity to psychostimulant drugs.
Abstract: The circadian clock comprises a set of genes involved in cell-autonomous transcriptional feedback loops that orchestrate the expression of a range of downstream genes, driving circadian patterns of behavior. Cognitive dysfunction, mood disorders, anxiety disorders and substance abuse disorders have been associated with disruptions in circadian rhythm and circadian clock genes, but the causal relationship of these associations is still poorly understood. In the present study, we investigate the effect of genetic disruption of the circadian clock, through deletion of both paralogs of the core gene cryptochrome (Cry1 and Cry2). Mice lacking Cry1 and Cry2 (Cry1-/-Cry2-/-) displayed attenuated dark phase and novelty-induced locomotor activity. Moreover, they showed impaired recognition memory but intact fear memory. Depression-related behaviors in the forced swim test or sucrose preference tests were unaffected but Cry1-/-Cry2-/- mice displayed increased anxiety in the open field and elevated plus maze tests. Finally, hyperlocomotion and striatal phosphorylation of extracellular signal-regulated kinase (ERK) induced by a single cocaine administration are strongly reduced in Cry1-/-Cry2-/- mice. Interestingly, only some behavioral measures were affected in mice lacking either Cry1 or Cry2. Notably, recognition memory was impaired in both Cry1-/-Cry2+/+ and Cry1+/+Cry2-/- mice. Moreover, we further observed elevated anxiety in Cry1-/-Cry2+/+ and Cry1+/+Cry2-/- mice. Our data indicate that beyond their role in the control of circadian rhythm, cryptochrome genes have a direct influence in cognitive function, anxiety-related behaviors and sensitivity to psychostimulant drugs.
TL;DR: This paper introduces an alternative account of how humans choose actions and guide locomotion in the presence of moving objects and shows how the new approach addresses the limitations of the bearing angle model and accounts for a variety of behaviors involving moving objects.
Abstract: Locomotion in complex dynamic environments is an integral part of many daily activities, including walking in crowded spaces, driving on busy roadways, and playing sports. Many of the tasks that humans perform in such environments involve interactions with moving objects -- that is, they require people to coordinate their own movement with the movements of other objects. A widely adopted framework for research on the detection, avoidance, and interception of moving objects is the bearing angle model, according to which observers move so as to keep the bearing angle of the object constant for interception and varying for obstacle avoidance. The bearing angle model offers a simple, parsimonious account of visual control but has several significant limitations and does not easily scale up to more complex tasks. In this paper, I introduce an alternative account of how humans choose actions and guide locomotion in the presence of moving objects. I show how the new approach addresses the limitations of the bearing angle model and accounts for a variety of behaviors involving moving objects, including (1) choosing whether to pass in front of or behind a moving obstacle, (2) perceiving whether a gap between a pair of moving obstacles is passable, (3) avoiding a collision while passing through single or multiple lanes of traffic, (4) coordinating speed and direction of locomotion during interception, (5) simultaneously intercepting a moving target while avoiding a stationary or moving obstacle, and (6) knowing whether to abandon the chase of a moving target. I also summarize data from recent studies that support the new approach.
TL;DR: In this paper, the authors evaluated whether there are different patterns of expression of the immediate early genes c-Fos and Zif-268 in these cortical areas after rats are exposed to object recognition tasks with different cognitive demands.
Abstract: Episodic memory reflects the capacity to recollect what, where and when a specific event happened in an integrative manner. Animal studies have suggested that the medial temporal lobe and the medial pre-frontal cortex are important for episodic-like memory formation. The goal of present study was to evaluate whether there are different patterns of expression of the immediate early genes c-Fos and Zif-268 in these cortical areas after rats are exposed to object recognition tasks with different cognitive demands. Male rats were randomly assigned to five groups: home cage control (CTR-HC), empty open field (CTR-OF), open field with one object (CTR-OF + Obj), novel object recognition task (OR) and episodic-like memory task (ELM) and were killed one hour after the last behavioral procedure. Rats were able to discriminate the objects in the OR task. In the ELM task, rats showed spatial (but not temporal) discrimination of the objects. We found an increase in the c-Fos expression in the dorsal dentate gyrus (DG) and in the perirhinal cortex (PRh) in the OR and ELM groups. The OR group also presented an increase of c-Fos expression in the medial prefrontal cortex (mPFC). Additionally, the OR and ELM groups had increased expression of Zif-268 in the mPFC. Moreover, Zif-268 was increased in the dorsal CA1 and perirhinal cortex only in the ELM group. In conclusion, the pattern of activation was different in tasks with different cognitive demands. Accordingly, correlation tests suggest the engagement of different neural networks in the object recognition tasks used. Specifically, perirhinal-dentate gyrus co-activation was detected after the what-where memory retrieval, but not after the novel object recognition task. Both regions correlated with the respective behavioral outcome. These findings can be helpful in the understanding of the neural networks underlying memory tasks with different cognitive demands.