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ENGELMANN, M., C. T. WOTJAK, I. NEUMANN, M. LUDWIG AND R. LANDGRAF. Behavioral consequences of intracerebral vasopressin and oxytocin: Focus on learning and memory. NEUROSCI BIOBEHAV REV 20(3)341–358, 1996.—Since the pioneering work of David de Wied and his colleagues, the neuropeptides arginine vasopressin and oxytocin have been thought to play a pivotal role in behavioral regulation in general, and in learning and memory in particular. The present review focuses on the behavioral effects of intracerebral arginine vasopressin and oxytocin, with particular emphasis on the role of these neuropeptides as signals in interneuronal communication. We also discuss several methodological approaches that have been used to reveal the importance of these intracerebral neuropeptides as signals within signaling cascades. The literature suggests that arginine vasopressin improves, and oxytocin impairs, learning and memory. However, a critical analysis of the subject indicates the necessity for a revision of this generalized concept. We suggest that, depending on the behavioral test and the brain area under study, these endogenous neuropeptides are differentially involved in behavioral regulation; thus, generalizations derived from a single behavioral task should be avoided. In particular, recent studies on rodents indicate that socially relevant behaviors triggered by olfactory stimuli and paradigms in which the animals have to cope with an intense stressor (e.g., foot-shock motivated active or passive avoidance) are controlled by both arginine vasopressin and oxytocin released intracerebrally. Copyright © 1996 Elsevier Science Ltd.

Research into the structure and function of the basal forebrain macrostructure called the extended amygdala (EA) has recently seen considerable growth. This paper reviews that work, with the objectives of identifying underlying themes and developing a common goal towards which investigators of EA function might work. The paper begins with a brief review of the structure and the ontological and phylogenetic origins of the EA. It continues with a review of research into the role of the EA in both aversive and appetitive states, noting that these two seemingly disparate avenues of research converge on the concept of reinforcement - either negative or positive - of adaptive responding. These reviews lead to a proposal as to where the EA may fit in the organization of the basal forebrain, and an invitation to investigators to place their findings in a unifying conceptual framework of the EA as a collection of neural ensembles that mediate adaptive responding.

This paper reviews evidence demonstrating a bidirectional relationship between memory and eating in humans and rodents. In humans, amnesia is associated with impaired processing of hunger and satiety cues, disrupted memory of recent meals, and overconsumption. In healthy participants, meal-related memory limits subsequent ingestive behavior and obesity is associated with impaired memory and disturbances in the hippocampus. Evidence from rodents suggests that dorsal hippocampal neural activity contributes to the ability of meal-related memory to control future intake, that endocrine and neuropeptide systems act in the ventral hippocampus to provide cues regarding energy status and regulate learned aspects of eating, and that consumption of hypercaloric diets and obesity disrupt these processes. Collectively, this evidence indicates that diet-induced obesity may be caused and/or maintained, at least in part, by a vicious cycle wherein excess intake disrupts hippocampal functioning, which further increases intake. This perspective may advance our understanding of how the brain controls eating, the neural mechanisms that contribute to eating-related disorders, and identify how to treat diet-induced obesity.

Sensory preconditioning protocols can be used to assess how the brain integrates memories that share common features. In these protocols, animals are first exposed to pairings of two relatively innocuous stimuli, S2 and S1 (stage 1), and then to pairings of one of these stimuli, S1, with an event of motivational significance (stage 2). Following this training, test presentations of S2 elicit responses appropriate to the motivationally significant event, and these responses are taken to indicate formation of distinct S2-S1 and S1-event memories that are integrated in some way to generate that responding. This paper reviews studies of sensory preconditioning in rats, mice, rabbits and people to determine whether S2-S1 and S1-event memories are integrated through a chaining process at the time of their retrieval (i.e., test presentations of S2 trigger retrieval of S1, and thereby, responses appropriate to the event); or “online” at the time of memory formation (i.e., in stage 2, S1 activates a representation of S2 such that both stimuli associate with the motivationally significant event). It finds that the type of integration is determined by the manner in which stimuli are presented in preconditioning as well as their familiarity. When the stimuli in preconditioning are presented repeatedly and/or serially (i.e., one after the other), the S2-S1 and S1-event memories are chained at the time of retrieval/testing. In contrast, when the stimuli in preconditioning are relatively novel and/or presented simultaneously, the S2-S1 and S1-event memories are integrated online. These statements are related to prior claims regarding the circumstances that promote different types of memory integration and, more generally, mechanisms of information processing in the mammalian brain.

In humans and other vertebrates, the range of disturbances and behavioural changes induced by spaceflight conditions are well known. Sensory organs and the central nervous system (CNS) are forced to adapt to new environmental conditions of weightlessness. In comparison with peripheral vestibular organs and behavioural disturbances in weightlessness conditions, the CNS vestibular centres of vertebrates, including the cerebellum, have been poorly examined in orbital experiments, as well as in experimental micro- and hypergravity. However, the cerebellum serves as a critical control centre for learning and sensory system integration during space-flight. Thus, it is referred to as a principal brain structure for adaptation to gravity and the entire sensorimotor adaptation and learning during weightlessness. This paper is focused on the prolonged spaceflight effects on the vestibular cerebellum evidenced from animal models used in the Bion-M1 project. The changes in the peripheral vestibular apparatus and brainstem primary vestibular centres with appropriate behavioural disorders after altered gravity exposure are briefly reviewed. The cerebellum studies in space missions and altered gravity are discussed.

Prediction error, defined by the discrepancy between real and expected outcomes, lies at the core of associative learning. Behavioural investigations have provided evidence that prediction error up- and down-regulates associative relationships, and allocates attention to stimuli to enable learning. These behavioural advances have recently been followed by investigations into the neurobiological substrates of prediction error. In the present paper, we review neuroscience data obtained using causal and recording neural methods from a variety of key behavioural designs. We explore the neurobiology of both appetitive (reward) and aversive (fear) prediction error with a focus on the mesolimbic dopamine system, the amygdala, ventrolateral periaqueductal gray, hippocampus, cortex and locus coeruleus noradrenaline. New questions and avenues for research are considered.

Benzodiazepine agonists stimulate feeding in animals. This paper reviews evidence which indicates that benzodiazepine-induced feeding is due to a specific enhancement of the perceived palatability of food and fluids, and is not a mere secondary consequence of anxiety reduction. In studies of the effect of benzodiazepines on affective reactions that are naturally elicited from rats by tastes, we have shown that (a) benzodiazepines enhance hedonic taste palatability in a receptor-specific fashion; (b) the relevant receptors and the minimal neural circuitry required to mediate benzodiazepine-induced palatability enhancement both exist complete in the decerebrate brain stem; and (c) even in normal brains, receptors in the brain stem, not forebrain, are the primary substrate for the benzodiazepine-induced enhancement of taste palatability. We conclude that a 'benzodiazepine-GABA' neural system in the brain stem constitutes an important component of the neural hierarchy responsible for taste pleasure. The reason why benzodiazepine tranquilizers have not been reported to enhance palatability for humans may be that the appropriate studies have not yet been done, that human doses are low, and that the brain stem palatability system is less responsive to commonly prescribed agonists that are anxiety/arousal benzodiazepine systems. Finally, in keeping with the purpose of the symposium in which this paper was originally presented, we discuss a number of issues regarding the measurement and interpretation of taste reactivity data.

The present paper provides an overview of dopamine (DA) and cholecystokinin (CCK) mechanisms that contribute to psychostimulant reward-related behaviors. Three different behavioral paradigms are focused on: intravenous psychostimulant reward, psychostimulant-induced locomotor activity, and psychostimulant-induced feeding. Based on evidence derived from these different behavioral paradigms, this paper reviews data indicating that nucleus accumbens CCK and DA play an important role in mediating reward. Neurobiological mechanisms are proposed to explain the functional relationship between CCK and DA in the nucleus accumbens.

The maternal behavior decline is important for the normal development of the young and the wellbeing of the mother. This paper reviews limited research on the factors and mechanisms involved in the rat maternal behavior decline and proposes a multi-level model. Framed in the parent-offspring conflict theory (an ultimate cause) and the approach-withdrawal model (a proximate cause), the maternal behavior decline is viewed as an active and effortful process, reflecting the dynamic interplay between the mother and her offspring. It is instigated by the waning of maternal motivation, coupled with the increased maternal aversion by the mother in responding to the changing sensory and motoric patterns of pup stimuli. In the decline phase, the neural circuit that mediates the inhibitory ("withdrawal") responses starts to increase activity and gain control of behavioral outputs, while the excitatory ("approach") maternal neural circuit is being inhibited or reorganized. Various hormones and certain monoamines may play a critical role in tipping the balance between the excitatory and inhibitory neural circuits to synchronize the mother-infant interaction.

Schizophrenia and Alzheimer’s disease impacts on various sensory processings are extensively reviewed in the present publication. This article describes aspects of a research project whose aim is to delineate the neurobiology that may underlie Social Withdrawal in Alzheimer’s disease, Schizophrenia and Major Depression. This is a European-funded IMI 2 project, identified as PRISM (Psychiatric Ratings using Intermediate Stratified Markers). This paper focuses specifically on the selected electrophysiological paradigms chosen based on a comprehensive review of all relevant literature and practical constraints. The choice of the electrophysiological biomarkers were fundamentality based their metrics and capacity to discriminate between populations. The selected electrophysiological paradigms are resting state EEG, auditory mismatch negativity, auditory and visual based oddball paradigms, facial emotion processing ERP’s and auditory steady-state response. The primary objective is to study the effect of social withdrawal on various biomarkers and endophenotypes found altered in the target populations. This has never been studied in relationship to social withdrawal, an important component of CNS diseases.

We are entering a new era of understanding human development with the ability to perform studies at the earliest time points possible. There is a substantial body of evidence to support the concept that early motor behaviour originates from supraspinal motor centres, reflects neurological integrity, and that altered patterns of behaviour may precede clinical manifestation of disease. Cine Magnetic Resonance Imaging (cineMRI) has established its value as a novel method to visualise motor behaviour in the human fetus, building on the wealth of knowledge gleaned from ultrasound sonography based studies. This paper presents a state of the art review incorporating findings from human and preclinical models, the insights from which, we propose, can proceed a reconceptualisation of fetal motor behaviour using advanced imaging techniques. Foremost is the need to better understand the role of the intrauterine environment, and its inherent unique set of stimuli that activate sensorimotor pathways and shape early brain development. Finally, an improved model of early motor development, combined with multimodal imaging, will provide a novel source of in utero biomarkers predictive of neurodevelopmental disorders.

THE following six papers derive from a satellite symposium held at the 23rd annual meeting of the Society for Neurosci- ence in Washington, D. C. on November 7, 1993. All articles in this meeting report were updated for currency and were subjected to peer review.T!~e purpose of the symposium "Be- havioral, Neural and Pharmacological Aspects of Palatabil- ity: Current Research on Taste Reactivity," was to inform investigators of recent advances in the assessment of palat- ability by the taste reactiviity test, devised by Grill and Nor- gren in (4,5). In his introduction to the symposium, Ralph Norgren referred to a single sentence in a grant proposal writ- ten about 20 years ago that proposed the use of a behavioral measure of orofacial reactions to assess the palatability of tastants. Shortly thereafter, Harvey Grill came to work in Norgren's laboratory at Rockefeller University where he de- veloped the taste reactivity test. Palatability is a difficult concept to define (15) but seems to be a hypothetical construct that is useful from a theoretical point of view (e.g.,16). Whether one partitions this concept into an intrinsic component (ingestant) and an associational component (ingestor) as suggested by Kissilef (11), or as a hedonic response to a taste stimulus based on an integration of taste, organism state, and prior associations (3), it is useful to have a metric which provides information about the mo- mentary behavioral reaction of the animal to the stimulus. The taste reactivity test serves as a tool for directly assess- ing the "palatability" of a flavored solution on the basis of operationally defined and quantifiable behavioral responses. By means of a permanently implanted intraoral cannula, a flavored solution is delivered across a rat's tongue while its orofacial and somatic responses are videotaped. On the basis of an extensive series of investigations, Grill and Norgren (4) determined that tastants that are normally preferred, such as sucrose solution, elicit iingestive reactions such as tongue protrusions (lateral and forward), mouth movements and paw licking. On the other hand, tastants that are normally avoided, such as quinine solution, elicit aversive reactions such as gaping, chin rubbing, paw treading, forelimb flailing and head shaking. Finally,. examination of the relationships between taste reactivity responses and intake measures in rats (17) has validated the importance of these behaviors in inges- tion. The taste reactivity test has been employed by a number of laboratories to directly index palatability. This methodologi- cal approach has been successfully used in both neural (e.g., 5-7) and pharmacological (e.g., 14) examinations of the con- trols of ingestive behavior. The taste reactivity methodology has several distinct attributes that make it well-suited for an analysis of palatability (8). First, the experimenter has explicit control of the stimulus delivery parameters. Second, taste re- sponsiveness can be measured in nondeprived animals. Third, the taste reactivity test can be used with a variety of neurologi- cal manipulations that render animals aphagic and adipsic (e.g., chronic decerebrate rats). Fourth, small volumes of the taste stimulus can be used to minimize the influence of postin- gestive events. Fifth, changes in behavior can be quantified past the point when animals would cease ingesting the stimu- lus fluid during an intake test. Finally, actual behavior is measured as opposed to the quantification of only the conse- quences of behavior (i.e., amount ingested). The symposium began with an introduction to the tech- nique by Ralph Norgren. This was followed an historical reflection on the development and refinement of the taste reactivity methodology by Harvey Grill and an overview of the importance of examining individual components of taste reactivity by Paul Breslin. The papers presented at this sympo- sium described the research of various investigators in North America (1,2,9,10,12,13) that are currently employing the taste reactivity test in their research programs. The goal of the symposium was to provide a forum for the discussion of collective research involving the taste reactivity methodology. The articles that follow represent the spirit of that discussion and offer broad range of insights into the psychobiological aspects of taste reactivity. In some ways the symposium seD'ed as an assessment of our progress in the conceptualization taste-elicited consummatory behavior. At least one fact re- mains clear. Since its inception as a systematic behavioral technique two decades ago, the taste reactivity methodology has repeatedly demonstrated its power as an anlytical tool that can promote a better understanding of both palatability and the neural control of ingestive behavior. Klaus-Peter Ossenkopp University of Western Ontario, London, Ontario, Canada Linda A. Parker University of Waterloo, Waterloo, Ontario, Canada, Alan C. Spector University of Florida, Gainesville, FL, USA 87

There is a wealth of data indicating that de novo protein S-nitrosylation in general and protein transnitrosylation in particular mediates the bulk of nitric oxide signalling. These processes enable redox sensing and facilitate homeostatic regulation of redox dependent protein signalling, function, stability and trafficking. Increased S-nitrosylation in an environment of increasing oxidative and nitrosative stress (O&NS) is initially a protective mechanism aimed at maintaining protein structure and function. When O&NS becomes severe, mechanisms governing denitrosylation and transnitrosylation break down leading to the pathological state referred to as hypernitrosylation (HN). Such a state has been implicated in the pathogenesis and pathophysiology of several neuropsychiatric and neurodegenerative diseases and we investigate its potential role in the development and maintenance of neuroprogressive disorders. In this paper, we propose a model whereby the hypernitrosylation of a range of functional proteins and enzymes lead to changes in activity which conspire to produce at least some of the core abnormalities contributing to the development and maintenance of pathology in these illnesses.

The locus coeruleus (LC), the major origin of noradrenergic modulation of the central nervous system, innervates extensive areas throughout the brain and is implicated in a variety of autonomic and cognitive functions. Alterations in the LC-noradrenergic system have been associated with healthy ageing and neuropsychiatric disorders including Parkinson's disease, Alzheimer's disease and depression. The last decade has seen advances in imaging the structure and function of the LC, and this paper systematically reviews the methodology and outcomes of sixty-nine structural and functional MRI studies of the LC in humans. Structural MRI studies consistently showed lower LC signal intensity and volume in clinical groups compared to healthy controls. Within functional studies, the LC was activated by a variety of tasks/stimuli and had functional connectivity to a range of brain regions. However, reported functional LC location coordinates were widely distributed compared to previously published neuroanatomical locations. Methodological and demographic factors potentially contributing to these differences are discussed, together with recommendations to optimize the reliability and validity of future LC imaging studies.

It is now well accepted that physical exercise stimulates hippocampal neurogenesis and may promote cognitive ability. Less clear are the mechanisms by which this process occurs. One potential contributing influence, that is usually neglected, is the vestibular system, which by its very nature must be activated during physical exercise and which essentially cannot be turned off without complete bilateral vestibular lesions. This paper reviews a small literature that demonstrates that bilateral vestibular loss (BVL) in rats modulates cell proliferation in the dentate gyrus (DG) and that artificial electrical activation of the vestibular system, using galvanic vestibular stimulation, does also. Although there are only a few piecemeal studies of this subject, because of the way that they were controlled, it is likely that the vestibular system has a regulatory role in cell proliferation in the DG and therefore possibly in neurogenesis, which needs to be taken into account in the interpretation of neurogenesis studies.

Several recent research findings indicate that schizophrenia (SCZ) may begin with an abnormal neuro-genesis from embryonic Neural Stem Cells (NSCs) and that this process may be particularly vulnerable to a number of genetic and/or environmental disturbances of early brain development. Since it is now well known that neurogenesis is not confined to the womb, but is a protracted process continuing in postnatal life well into adolescence and beyond, and since in the majority of subjects diagnosed with SCZ the first psychotic break occurs in late adolescence or early adulthood, the aim of our paper is to summarize the main findings supporting a possible link between changes in developmental postnatal neurogenesis and SCZ, with a specific focus on the critical period of adolescence and associated environmental risk factors. Establishing a significant role of adult neurogenesis in the emergence of psychosis will help us not only to better understand the pathogenesis of this neuopsychiatric disorder, but also to provide the key to potential strategies toward possible treatments and/or early corrective interventions.

Functional magnetic resonance imaging (fMRI) studies regularly use univariate general-linear-model-based analyses (GLM). Their findings are often inconsistent across different studies, perhaps because of several fundamental brain properties including functional heterogeneity, balanced excitation and inhibition (E/I), and sparseness of neuronal activities. These properties stipulate heterogeneous neuronal activities in the same voxels and likely limit the sensitivity and specificity of GLM. This paper selectively reviews findings of histological and electrophysiological studies and fMRI spatial independent component analysis (sICA) and reports new findings by applying sICA to two existing datasets. The extant and new findings consistently demonstrate several novel features of brain functional organization not revealed by GLM. They include overlap of large-scale functional networks (FNs) and their concurrent opposite modulations, and no significant modulations in activity of most FNs across the whole brain during any task conditions. These novel features of brain functional organization are highly consistent with the brain's properties of functional heterogeneity, balanced E/I, and sparseness of neuronal activity, and may help reconcile inconsistent GLM findings.

Background This systematic review provides an overview of the literature deducing information about brain activation during (1) imagined walking using MRI/fMRI or (2) during real walking using measurement systems as fNIRS, EEG and PET. Methods Three independent reviewers undertook an electronic database research browsing six databases. The search request consisted of three search fields. The first field comprised common methods to evaluate brain activity. The second search field comprised synonyms for brain responses to movements. The third search field comprised synonyms for walking. Results 48 of an initial yield of 1832 papers were reviewed. We found differences in cortical activity regarding young vs. old individuals, physically fit vs. physically unfit cohorts, healthy people vs. patients with neurological diseases, and between simple and complex walking tasks. Conclusions We summarize that the dimension of brain activity in different brain areas during walking is highly sensitive to task complexity, age and pathologies supporting previous assumptions underpinning the significance of cortical control. Many compensation mechanisms reflect the brain's plasticity which ensures stable walking.

Modulating neuronal activity by electrical stimulation has expanded from the realm of motor indications into the field of psychiatric disorders in the past 10 years. The medial forebrain bundle (MFB), with a seminal role in motor, reward orientated and affect regulation behaviors, and its afferent and efferent loci, have been targeted in several DBS trials in patients with psychiatric disorders. However, little is known about the consequences of modulating the MFB in affective disorders. The paper reviews the relevant pre-clinical literature investigating electrical stimulation of regions associated with the MFB in the context of several models of psychiatric disorders, in particular depression. The clinical data is promising but limited, and pre-clinical studies are essential for improved understanding of the anatomy, the connectivity, and the consequences of stimulation of the MFB and regions associated with the neurocircuitry of psychiatric disorders. Current data suggests that the MFB is at a "privileged" position on this circuitry and its stimulation can simultaneously modulate activity at other key sites, such as the nucleus accumbens, the ventromedial prefrontal cortex or the ventral tegmental area. Future experimental work will need to shed light on the anti-depressive mechanisms of MFB stimulation in order to optimize clinical interventions.

The aims of the paper are to update Rolls' quantitative computational theory of hippocampal function and the predictions it makes about the different subregions (dentate gyrus, CA3 and CA1), and to examine behavioral and electrophysiological data that address the functions of the hippocampus and particularly its subregions. Based on the computational proposal that the dentate gyrus produces sparse representations by competitive learning and via the mossy fiber pathway forces new representations on the CA3 during learning (encoding), it has been shown behaviorally that the dentate gyrus supports spatial pattern separation during learning. Based on the computational proposal that CA3-CA3 autoassociative networks are important for episodic memory, it has been shown behaviorally that the CA3 supports spatial rapid one-trial learning, learning of arbitrary associations where space is a component, pattern completion, spatial short-term memory, and spatial sequence learning by associations formed between successive items. The concept that the CA1 recodes information from CA3 and sets up associatively learned backprojections to neocortex to allow subsequent retrieval of information to neocortex, is consistent with findings on consolidation. Behaviorally, the CA1 is implicated in processing temporal information as shown by investigations requiring temporal order pattern separation and associations across time; and computationally this could involve associations in CA1 between object and timing information that have their origins in the lateral and medial entorhinal cortex respectively. The perforant path input from the entorhinal cortex to DG is implicated in learning, to CA3 in retrieval from CA3, and to CA1 in retrieval after longer time intervals ("intermediate-term memory") and in the temporal sequence memory for objects.

This paper systematically reviews the literature pertaining to the use of resting-state functional magnetic resonance imaging (rsfMRI) in anorexia nervosa (AN), classifying studies on the basis of different analysis approaches. We followed PRISMA guidelines. Fifteen papers were included, investigating a total of 294 participants with current or past AN and 285 controls. The studies used seed-based, whole-brain independent component analysis (ICA), network-of-interest ICA based and graph analysis approaches. The studies showed relatively consistent overlap in results, yet little overlap in their analytical approach and/or a-priori assumptions. Functional connectivity alterations were mainly found in the corticolimbic circuitry, involved in cognitive control and visual and homeostatic integration. Some overlapping findings were found in brain areas putatively important in AN, such as the insula. These results suggest altered functional connectivity in networks/areas linked to the main symptom domains of AN, such as impaired cognitive control and body image disturbances. These preliminary evidences suggest that more targeted treatments need to be developed that focus on these two symptom domains. Further studies with multi-approach analyses and longitudinal designs are needed to better understand the complexity of AN.

This article reviews the anatomical connections of the paraventricular nucleus of the thalamus (PVT) and discusses some of the connections by which the PVT could influence behavior. The PVT receives neurochemically diverse projections from the brainstem and hypothalamus with an especially strong innervation from peptide producing neurons. Anatomical evidence is also presented which suggests that the PVT relays information from neurons involved in visceral or homeostatic functions. In turn, the PVT is a major source of projections to the nucleus accumbens, the bed nucleus of the stria terminalis and the central nucleus of the amygdala as well as the cortical areas associated with these subcortical regions. The PVT is activated by conditions and cues that produce states of arousal including those with appetitive or aversive emotional valences. The paper focuses on the potential contribution of the PVT to circadian rhythms, fear, anxiety, food intake and drug-seeking. The information in this paper highlights the potential importance of the PVT as being a component of the brain circuits that regulate reward and defensive behavior with the hope of generating more research in this relatively understudied region of the brain.

For human and non-human primates, vision is one of the most privileged sensory channels used to interact with the environment. The importance of vision is strongly embedded in the organization of the primate brain as about one third of its cortical surface is involved in visual functions. It is therefore not surprising that the absence of vision from birth, or the loss of vision later in life, has huge consequences, both anatomically and functionally. Studies in animals and humans, conducted over the past few decades, have demonstrated that the absence of vision causes massive structural changes that take place not only in the visually deprived cortex but also in other brain areas. These studies have further shown that the visually deprived cortex becomes responsive to a wide variety of non-visual sensory inputs. Recent studies even showed a role of the visually deprived cortex in cognitive processes. At the behavioral level, increases in acuity for auditory and tactile processes have been reported. The study of the congenitally blind brain also offers a unique model to gain better insights into the functioning of the normal sighted brain and to understand to what extent visual experience is necessary for the brain to develop its functional architecture. Finally, the study of the blind brain allows us to investigate how consciousness develops in the absence of vision. How does the brain of someone who has never had any visual perception form an image of the external world? In this paper, we discuss recent findings from animal studies as well as from behavioural and functional brain imaging studies in sighted and blind individuals that address these questions.

Motor imagery (MI) or the mental simulation of action is now increasingly being studied using neuroimaging techniques such as positron emission tomography and functional magnetic resonance imaging. The booming interest in capturing the neural underpinning of MI has provided a large amount of data which until now have never been quantitatively summarized. The aim of this activation likelihood estimation (ALE) meta-analysis was to provide a map of the brain structures involved in MI. Combining the data from 75 papers revealed that MI consistently recruits a large fronto-parietal network in addition to subcortical and cerebellar regions. Although the primary motor cortex was not shown to be consistently activated, the MI network includes several regions which are known to play a role during actual motor execution. The body part involved in the movements, the modality of MI and the nature of the MI tasks used all seem to influence the consistency of activation within the general MI network. In addition to providing the first quantitative cortical map of MI, we highlight methodological issues that should be addressed in future research.

Body image distortion is a key symptom of anorexia nervosa (AN). The majority of the neuroimaging studies on body image distortion in AN conceptualized it as an unidimensional symptom. However, behavioural research considers such symptom as a multidimensional construct. Our paper systematically reviews the functional magnetic resonance (fMRI) studies on body image distortion in AN and classifies them according to a speculative model of body image distortion, that consists of the three most widely accepted components in the behavioural research: perceptive, affective and cognitive. We found that: (1) the perceptive component is mainly related to alterations of the precuneus and the inferior parietal lobe; (2) the affective component is mainly related to alterations of the prefrontal cortex, the insula and the amygdala; (3) the cognitive component has been weakly explored. These evidences seem to confirm that specific neural alterations are related to the components of the body image distortion in AN. Further neuroimaging studies are needed to better understand the complexity of the body image distortion in AN.

N-methyl-D-aspartate receptors (NMDARs) are key components of neural signaling, playing roles in synaptic transmission and in the synaptic plasticity thought to underlie learning and memory. NMDAR activation can also have neurotoxic consequences contributing to several forms of neurodegeneration. Additionally, NMDARs can modulate neuronal function and regulate the ability of synapses to undergo synaptic plasticity. Evidence gathered over the past 20 years strongly supports the idea that untimely activation of NMDARs impairs the induction of long-term potentiation (LTP) by a form of metaplasticity. This metaplasticity can be triggered by multiple stimuli including physiological receptor activation, and metabolic and behavioral stressors. These latter findings raise the possibility that NMDARs contribute to cognitive dysfunction associated with neuropsychiatric disorders. This paper examines NMDAR metaplasticity and its potential role in cognition. Recent studies using NMDAR antagonists for therapeutic purposes also raise the possibility that metaplasticity may contribute to clinical effects of certain drugs.

a b s t r a c t The intimate connection between the brain and the heart was enunciated by Claude Bernard over 150 years ago. In our neurovisceral integration model we have tried to build on this pioneering work. In the present paper we further elaborate our model and update it with recent results. Specifically, we per- formed a meta-analysis of recent neuroimaging studies on the relationship between heart rate variability and regional cerebral blood flow. We identified a number of regions, including the amygdala and ventro- medial prefrontal cortex, in which significant associations across studies were found. We further propose that the default response to uncertainty is the threat response and may be related to the well known neg- ativity bias. Heart rate variability may provide an index of how strongly 'top-down' appraisals, mediated by cortical-subcortical pathways, shape brainstem activity and autonomic responses in the body. If the default response to uncertainty is the threat response, as we propose here, contextual information repre- sented in 'appraisal' systems may be necessary to overcome this bias during daily life. Thus, HRV may serve as a proxy for 'vertical integration' of the brain mechanisms that guide flexible control over behavior with peripheral physiology, and as such provides an important window into understanding stress and health.

The anterior cingulate cortex (ACC) is a ubiquitously active brain region, doubtless reflecting a multiplicity of functions. Improved knowledge of such functions should progress understanding of disorders with established ACC involvement, including depression, apathy, and addiction. This theoretical paper proposes a hypothesis concerning an original and important ACC function, namely that the ACC operates as part of distributed networks to which it contributes the representation of requirements. Such requirements are further suggested to proactively coordinate and organize processing in effector regions to achieve consummation, thereby implementing an optimal strategy. The ACC (predominantly Brodmann's areas 24 and 32) is activated during states characterized by active requirements such as homeostatic perturbations, pain, desire, addiction, and cognition, and this is evidenced by systematic reviews of neuroimaging studies, and by neuropsychological findings. Further, ACC activity commences early in processing, and proactively influences processing in effector regions, further supporting the hypothesis. Thus, this hypothesis accounts for some ACC findings that are otherwise unexplained, and proposes novel testable predictions offering new insights into ACC functional organization.

A particularly prominent model of auditory cortical function proposes that a dorsal brain pathway, emanating from the posterior auditory cortex, is primarily concerned with processing the spatial features of sounds. In the present paper, we outline some difficulties with a strict functional interpretation of this pathway, and highlight the recent trend to understand this pathway in terms of one that uses acoustic information to guide motor output towards objects of interest. In this spirit, we consider the possibility that some of the auditory spatial processing activity that has been observed in the dorsal pathway may actually be understood as a form of action processing in which the visual system may be guided to a particular location of interest. In this regard, attentional orientation may be considered a low-level form of action planning. Incorporating an auditory-guided motor aspect to the dorsal pathway not only offers a more holistic account of auditory processing, but also provides a more ecologically valid perspective on auditory processing in dorsal brain regions.

The present review describes and analyzes several recent papers in which the processes of preparation, evaluation and changing a cue's predictive value on a trial-by-trial basis conform a cycle that permits behavior to be constantly updated. This approach is an extension of Joaquin Fuster's proposal of a “perception–action” cycle in which executive networks are constantly updated as a function of the trials’ outcome. The presented results can also be considered in relation to the computational Bayesian brain framework proposed by Friston (2009) . The present approach is based on human electrophysiological studies of Posner's central cue paradigm, which provides the possibility to dissociate the following processing steps: (i) preparation for certain stimuli, (ii) evaluation of the validity or invalidity of the preparatory state, and (iii) the feedback cycling of the information extracted from one trial to the next. This trial-by-trial learning would be a potential basis for organism adaptation.

Scopolamine is used as a standard/reference drug for inducing cognitive deficits in healthy humans and animals. Effects are often interpreted in terms of a role of acetylcholine in mnemonic and/or attentional processes. In this paper an overview is given of the effects of scopolamine on animal behavior. Examination of the dose-response curve of systemically administered scopolamine indicates that sensory discrimination and attention are most sensitive to disruption. When higher doses (>0.03mg/kg) are used, deficits in other cognitive and non-cognitive functions (e.g., learning and memory, locomotor activity) are reported. Several behavioral processes (taste aversion, anxiety, short-term memory, attention) are found to be affected after intracerebral injections of scopolamine. It is concluded that effects on learning and memory performance which are observed after higher doses of scopolamine are mediated by (1) primary effects on attention and sensory/stimulus discrimination, (2) non-specific effects on behavior (e.g., locomotor activity, anxiety), and (3) peripheral side-effects (e.g., pupil dilation, salivation). Finally, the validity of scopolamine as a pharmacological model for cognitive impairment is discussed. The use of muscarinic M1 antagonists is suggested as a more selective and effective way of inducing cholinergic-induced cognitive deficits.

During the early post-natal phases the brain is experience-seeking and provided by a considerable plasticity which allows a fine tuning between the external environment and the developing organism. Since the early work of Seymour Levine, an impressive amount of research has clearly shown that stressful experiences exert powerful effects on the brain and body development. These effects can last throughout the entire life span influencing brain function and increasing the risk for depression and anxiety disorders. The mechanisms underlying the effects of early stress on the developing organism have been widely studied in rodents through experimental manipulations of the post-natal environment, such as handling, which have been shown to exert important effects on the emotional phenotype and the response to stress. In the present paper we review the relevant literature and present some original data indicating that, compared to handling, which imposes an external manipulation on the mother-infant relationship, social enrichment, in the form of communal rearing, in mice has very profound effects on animal's emotionality and the response to stress. These effects are also accompanied by important changes in central levels of brain-derived neurotrophic factor. The present data indicate that communal rearing has more pervasive effects than handling, strengthening previous data suggesting that it is a good animal model of reduced susceptibility to depression-like behavior. Overall, the availability of ever more sophisticated animal models represents a fundamental tool to translate basic research data into appropriate interventions for humans raised under traumatic or impoverished situations.

I examine evidence that the concentration of certain modulatory neurotransmitters varies across species, including differences between rodents and primates. Microdialysis studies indicate that the baseline concentration of serotonin, norepinephrine, dopamine, and acetylcholine, as measured in the prefrontal cortex of awake animals, may differ between rats and macaque monkeys. These differences may extend to mice and humans, as well. If there are differences in the tonic concentration of these neurotransmitters, this may affect the functioning of these transmitter systems in multiple ways, including potential effects on neuropsychiatric conditions such as the various mental illnesses and modeling of them in animals. Species differences in transmitter concentration may also have neuropharmacological implications, and may be relevant to the phenomenon of differences in speed of drug response between humans and rodents. This paper is divided into three sections that address related questions about the potential concentration differences: (1) Are there species differences in baseline neurotransmitter concentration? (2) Are the putative differences functional? (3) What might the functional differences be? Consideration of the existing evidence indicates that there may indeed be functional species differences in the modulatory transmitter systems.

The intimate connection between the brain and the heart was enunciated by Claude Bernard over 150 years ago. In our neurovisceral integration model we have tried to build on this pioneering work. In the present paper we further elaborate our model. Specifically we review recent neuroanatomical studies that implicate inhibitory GABAergic pathways from the prefrontal cortex to the amygdala and additional inhibitory pathways between the amygdala and the sympathetic and parasympathetic medullary output neurons that modulate heart rate and thus heart rate variability. We propose that the default response to uncertainty is the threat response and may be related to the well known negativity bias. We next review the evidence on the role of vagally mediated heart rate variability (HRV) in the regulation of physiological, affective, and cognitive processes. Low HRV is a risk factor for pathophysiology and psychopathology. Finally we review recent work on the genetics of HRV and suggest that low HRV may be an endophenotype for a broad range of dysfunctions.

The aim of this paper is to review evidences that stressful events throughout life can have a long-term impact on ageing and the progression of Alzheimer's disease. As early as the prenatal or neonatal period, stress can alter the rate of cognitive decline and neurodegenerative changes in the brain in a stressor-dependent manner, with prenatal restraint and maternal separation usually causing damage to the brain, whereas neonatal handling was found protective. The occurrence of negative outcomes of early stress can, however, be reversed by subsequent events known to be beneficial to the ageing process. After the early developmental period, it is currently unknown how stress will impact on the ageing process, due to a lack of studies. On the other hand, there is evidence of a lack of plasticity of the brain monoaminergic systems in response to stress with age, and of age-dependent changes in the immediate impact of stress, which is greater in subjects vulnerable to age-related cognitive decline. In addition, vulnerability to stress enhances the risk of developing Alzheimer's disease in humans and chronic substantial stress in animal models of the disease accelerates both the onset and progression of pathological markers in the brain. In an attempt to integrate these findings, a hypothesis is presented here whereby stress, in susceptible individuals, would precipitate age-related cognitive decline and hippocampal integrity during normal and pathological ageing, but will only affect the progression of pathological markers of Alzheimer's disease in the presence of other risk factors to this neuropathological disorder.

The benchmark discovery of the cingulate gyrus as a brain structure receiving stimuli from muscles and viscera (proprioception and interoception) is traced to a 1907/1908 article by neuropathologist Christfried Jakob. Further, the involvement of the mamillary bodies, anterior thalamic nucleus, cingulate cortex and hippocampus in the circuitry of the emotive brain (i.e. all elements of the 1937 'circuit of Papez') was published by Jakob in his 1911 and 1913 monographs on human and comparative neuroanatomy. In those works, Jakob also described the thalamocingulate projection, commonly attributed to a 1933 study by Le Gros Clark and Boggon, and introduced the term 'visceral brain', commonly attributed to a 1949 paper by MacLean. The present article includes the first English translations of Jakob's relevant passages, which incontrovertibly document his chronological priority in discovering the visceral brain and some of its key constituent elements.

Amphetamines, including methamphetamine, pose a significant cost to society due to significant numbers of amphetamine-abusing individuals who suffer major health-related consequences. In addition, methamphetamine use is associated with heightened rates of violent and property-related crimes. The current paper reviews the existing literature addressing genetic differences in mice that impact behavioral responses thought to be relevant to the abuse of amphetamine and amphetamine-like drugs. Summarized are studies that used inbred strains, selected lines, single-gene knockouts and transgenics, and quantitative trait locus (QTL) mapping populations. Acute sensitivity, neuroadaptive responses, rewarding and conditioned effects are among those reviewed. Some gene mapping work has been accomplished, and although no amphetamine-related complex trait genes have been definitively identified, translational work leading from results in the mouse to studies performed in humans is beginning to emerge. The majority of genetic investigations have utilized single-gene knockout mice and have concentrated on dopamine- and glutamate-related genes. Genes that code for cell support and signaling molecules are also well-represented. There is a large behavioral genetic literature on responsiveness to amphetamines, but a considerably smaller literature focused on genes that influence the development and acceleration of amphetamine use, withdrawal, relapse, and behavioral toxicity. Also missing are genetic investigations into the effects of amphetamines on social behaviors. This information might help to identify at-risk individuals and in the future to develop treatments that take advantage of individualized genetic information.

Cyrulnik, S.C., and V.J. Hinton. Duchenne muscular dystrophy: A cerebellar disorder? NEUROSCI. BIOBEHAV. REV. Duchenne muscular dystrophy (DMD) is a genetic disorder that is often associated with cognitive deficits. These cognitive deficits have been linked to the absence of dystrophin, a protein product which is normally found in multiple tissues throughout the body. In the current paper, we argue that it is the absence of dystrophin in the cerebellum that is responsible for the cognitive deficits observed. We begin by reviewing data that document structural and functional abnormalities in the brains of individuals with DMD and mdx mice. We briefly review the cognitive deficits associated with DMD, and then present neuroimaging and neuropsychological evidence to indicate that the cerebellum is involved in the same aspects of cognition that are impaired in children with DMD. It is our contention that the development of brain pathways in the cerebellum (e.g., cerebro-cerebellar loops) without dystrophin may result in altered brain function presenting as cognitive deficits in DMD.

The study of 5-hydroxytryptamine (5-HT) systems has benefited from the identification, classification and cloning of multiple 5-HT receptors (5-HT(1)-5-HT(7)). Increasing evidence suggests that 5-HT pathways, reuptake site/transporter complex and 5-HT receptors represent a strategic distribution for learning and memory. A key question still remaining is whether 5-HT markers (e.g., receptors) are directly or indirectly contributing to the physiological and pharmacological basis of memory and its pathogenesis or, rather, if they represent protective or adaptable mechanisms (at least in initial stages). In the current paper, the major aim is to revise recent advances regarding mammalian 5-HT(1A) receptors in light of their physiological, pathophysiological and therapeutic implications in memory. An attempt is made to identify and discuss sources of discrepancies by employing an analytic approach to examine the nature and degree of difficulty of behavioral tasks used, as well as implicating other factors (for example, brain areas, training time or duration, and drug administration) which might offer new insights into the understanding and interpretation of these data. In this context, 8-OH-DPAT deserves special attention since for many years it has been the more selective 5-HT drug and, hence, more frequently used. As 5-HT(1A) receptors are key components of serotonergic signaling, investigation of their memory mechanisms and action sites and the conditions under which they might operate, could yield valuable insights. Moreover, selective drugs with agonists, neutral antagonists or inverse agonist properties for 5-HT(1A) (and 5-HT(7)) receptors may constitute a new therapeutic opportunity for learning and memory disorders.

The phenomenon of medial forebrain bundle self-stimulation offers a powerful model of reward-based behavior. In particular, it appears to activate a neural system whose natural function is to compute the survival value or utility of present stimuli and to help orchestrate responses toward those inputs. Although the anatomical identity of this system is as yet unknown, recent descriptions of anatomical macrosystems within the basal forebrain lead to the proposal that it may be largely contained within the central extended amygdala network. This paper reviews decades' worth of behavioral and neurophysiological investigations of brain stimulation reward that support or are at least consistent with this idea. The proposed network circuitry underlying self-stimulation is also placed into the larger context of basal forebrain function, specifically, the role of the ventral striatopallidum in linking motivation to behavior, the role of the amygdala in detecting motivationally significant inputs, and the role of the magnocellular complex in communicating reward information to cortical and hippocampal targets.

Epilepsy is frequently associated with cognitive impairments which result from various interacting factors. The present paper deals with the contribution of neuropsychology to the characterization of the type of epilepsy and the possible mechanisms underlying idiopathic epileptic syndromes. The non-lesional, so-called idiopathic epilepsies, constitute an interesting model for assessing the relationship between epileptiform EEG discharges and cognition. Among the idiopathic generalized epilepsies, disorders of social integration and personality have been frequently reported in juvenile myoclonic epilepsy (JME). Since similar disturbances are observed in frontal-lobe-lesioned patients, impairments in other frontal lobe functions (e.g. executive functions) might be expected in JME. This gives rise to speculation about the possible underlying pathophysiological mechanisms in JME. With regard to partial idiopathic epilepsies, benign childhood epilepsy with centrotemporal spikes (BCECTS) may provide a useful model for the study of the relationship between epileptiform EEG discharges in the peri-sylvian region and language functions. Furthermore, the description of mild cognitive dysfunctions in BCECTS, and their persistence into adulthood, can provide information about compensatory mechanisms and may allow for the generation of remedial strategies. Thus, 'lesional' neuropsychology has given way to 'dynamic' neuropsychology based on specific postulates. By using the cognitive profile to specify the mechanism underlying the behavioral disturbances observed in different types of epilepsy, neuropsychology may eventually contribute to a revision of the present classification of epileptic syndromes. In addition, the neuropsychological data may help predict the extent and limits of functional recovery and cerebral plasticity.

The phenotypic expression of behaviour is the outcome of interacting neuronal networks and is modulated by different subcortical systems. In the present paper the role of a major subcortical neurochemical system, dopamine (DA), is reviewed. In particular, knockout (KO) technology has given an overwhelming insight into the effects of specific component of the dopaminergic system. Therefore, the behavioural profile of dopamine transporter (DAT), tyrosine hydroxylase (TH), DA and cAMP-regulated phosphoprotein (DARPP 32), and D1, D2, D3, D4 and D5 dopamine receptors knockouts (and their combination) is reviewed.TH, D1, D2, D4 KO mice exhibit decreased locomotor activity, perhaps due to decreased motivational level. D3 KO and DAT KO mice show an increase in basal and novelty-induced activity respectively. It is possible that the increased dopamine levels in DAT KO mice enhance motivation. These observations support the hyperDA hypothesis in hyperactive phenotypes. Moreover, they suggest that the inhibitory effect of psychostimulant drugs, such as methylphenidate and amphetamines, in Attention Deficit Hyperactivity Disorder may be the outcome of an altered balance between auto- and hetero-receptors. However, since KO technology is hampered by blockade of the target at early stages of development, some alternatives have been proposed, such as inducible mutagenesis and inhibitory small RNAs conveyed to target by viral vectors in adulthood.

There is evidence that abnormalities within the dopamine system in the brain play a major role in the pathophysiology of attention deficit hyperactivity disorder (ADHD). For instance, dopaminergic psychostimulants, the drugs of first choice in ADHD, interact directly with the dopamine transporter (DAT). Molecular genetic studies suggest involvement of a polymorphism of the DAT gene in ADHD. More recent imaging studies show abnormalities in various brain structures, but particularly in striatal regions. In the current paper we review recent studies in this area. First in vivo measurements of DAT with single photon emission computed tomography (SPECT) in ADHD patients revealed an elevation of striatal DAT density. No differences in DAT density between the left and right side and between putamen and caudate nucleus have been found in [99mTc]TRODAT-1 SPECT of ADHD patients. Patients with ADHD and with a history of nicotine abuse both displayed lower values of DAT density in [99mTc]TRODAT-1 SPECT than non-smokers with ADHD. DAT seem to be elevated in non-smoking ADHD patients suffering from the purely inattentive subtype of ADHD as well as in those with the combined or purely hyperactive/impulsive subtype.