The ability to detect unexpected novel stimuli is crucial for survival, as it might urge a prompt adaptive response. Human auditory novelty detection has been associated to the mismatch negativity long-latency auditory-evoked potential, peaking at 100-200 ms. Yet, recent animal studies showing novelty responses at a very short latency (about 20-30 ms) in individual neurons already at the level of the midbrain and thalamus suggest that novelty detection might be a basic principle of the functional organization of the auditory system, expanding from lower levels in the brainstem along the auditory pathway up to higher-order areas of the cerebral cortex. To test this suggestion, we here measured auditory brainstem and middle latency response (MLR) to frequency novel stimuli embedded in an oddball sequence. To oversee refractoriness confounds a 'control block' was used. The results showed that occasional changes in auditory frequency information were detected as early as 30 ms (Pa waveform of the MLR) after stimulus onset. The control block precluded these effects as resulting merely from refractoriness, altogether supporting the notion of 'true' early auditory change detection in humans, matching the latency range of auditory novelty responses described in individual neurons of subhuman species. Our results suggest that auditory change detection of frequency information is a multistage process that occurs at the primary auditory cortex and is transmitted to the higher levels of the auditory pathway.
Reward contains separable psychological components of learning, incentive motivation and pleasure. Most computational models have focused only on the learning component of reward, but the motivational component is equally important in reward circuitry, and even more directly controls behavior. Modeling the motivational component requires recognition of additional control factors besides learning. Here I discuss how mesocorticolimbic mechanisms generate the motivation component of incentive salience. Incentive salience takes Pavlovian learning and memory as one input and as an equally important input takes neurobiological state factors (e.g. drug states, appetite states, satiety states) that can vary independently of learning. Neurobiological state changes can produce unlearned fluctuations or even reversals in the ability of a previously learned reward cue to trigger motivation. Such fluctuations in cue‐triggered motivation can dramatically depart from all previously learned values about the associated reward outcome. Thus, one consequence of the difference between incentive salience and learning can be to decouple cue‐triggered motivation of the moment from previously learned values of how good the associated reward has been in the past. Another consequence can be to produce irrationally strong motivation urges that are not justified by any memories of previous reward values (and without distorting associative predictions of future reward value). Such irrationally strong motivation may be especially problematic in addiction. To understand these phenomena, future models of mesocorticolimbic reward function should address the neurobiological state factors that participate to control generation of incentive salience. Reward contains separable psychological components of learning, incentive motivation and pleasure. Most computational models have focused only on the learning component of reward, but the motivational component is equally important in reward circuitry, and even more directly controls behavior.
As a chemical transmitter in the mammalian central nervous system, nitric oxide (NO) is still thought a bit of an oddity, yet this role extends back to the beginnings of the evolution of the nervous system, predating many of the more familiar neurotransmitters. During the 20 years since it became known, evidence has accumulated for NO subserving an increasing number of functions in the mammalian central nervous system, as anticipated from the wide distribution of its synthetic and signal transduction machinery within it. This review attempts to probe beneath those functions and consider the cellular and molecular mechanisms through which NO evokes short- and long-term modifications in neural performance. With any transmitter, understanding its receptors is vital for decoding the language of communication. The receptor proteins specialised to detect NO are coupled to cGMP formation and provide an astonishing degree of amplification of even brief, low amplitude NO signals. Emphasis is given to the diverse ways in which NO receptor activation initiates changes in neuronal excitability and synaptic strength by acting at pre- and/or postsynaptic locations. Signalling to non-neuronal cells and an unexpected line of communication between endothelial cells and brain cells are also covered. Viewed from a mechanistic perspective, NO conforms to many of the rules governing more conventional neurotransmission, particularly of the metabotropic type, but stands out as being more economical and versatile, attributes that presumably account for its spectacular evolutionary success.
This review discusses the evidence for the hypothesis that the development of drug addiction can be understood in terms of interactions between Pavlovian and instrumental learning and memory mechanisms in the brain that underlie the seeking and taking of drugs. It is argued that these behaviours initially are goal‐directed, but increasingly become elicited as stimulus–response habits by drug‐associated conditioned stimuli that are established by Pavlovian conditioning. It is further argued that compulsive drug use emerges as the result of a loss of prefrontal cortical inhibitory control over drug seeking habits. Data are reviewed that indicate these transitions from use to abuse to addiction depend upon shifts from ventral to dorsal striatal control over behaviour, mediated in part by serial connectivity between the striatum and midbrain dopamine systems. Only some individuals lose control over their drug use, and the importance of behavioural impulsivity as a vulnerability trait predicting stimulant abuse and addiction in animals and humans, together with consideration of an emerging neuroendophenotype for addiction are discussed. Finally, the potential for developing treatments for addiction is considered in light of the neuropsychological advances that are reviewed, including the possibility of targeting drug memory reconsolidation and extinction to reduce Pavlovian influences on drug seeking as a means of promoting abstinence and preventing relapse. Corticostriatal circuitry mediating the influence of drug‐associated conditioned stimuli on drug seeking actions and habits. Interactions between ventral and dorsal striatum via serial connections with midbrain dopamine neurons mediate the progressive shift to control over drug seeking habits by the dorsal striatum that eventually become compulsive through the loss of top‐down inhibitory control by prefrontal cortical areas.
Autophagy is a lysosomal degradative process which recycles cellular waste and eliminates potentially toxic damaged organelles and protein aggregates. The important cytoprotective functions of autophagy are demonstrated by the diverse pathogenic consequences that may stem from autophagy dysregulation in a growing number of neurodegenerative disorders. In many of the diseases associated with autophagy anomalies, it is the final stage of autophagy–lysosomal degradation that is disrupted. In several disorders, including A lzheimer's disease ( AD ), defective lysosomal acidification contributes to this proteolytic failure. The complex regulation of lysosomal p H makes this process vulnerable to disruption by many factors, and reliable lysosomal p H measurements have become increasingly important in investigations of disease mechanisms. Although various reagents for p H quantification have been developed over several decades, they are not all equally well suited for measuring the p H of lysosomes. Here, we evaluate the most commonly used p H probes for sensitivity and localisation, and identify L yso S ensor yellow/blue‐dextran, among currently used probes, as having the optimal profile of properties for measuring lysosomal p H . In addition, we review evidence that lysosomal acidification is defective in AD and extend our original findings, of elevated lysosomal p H in presenilin 1 ( PS 1)‐deficient blastocysts and neurons, to additional cell models of PS 1 and PS 1/2 deficiency, to fibroblasts from AD patients with PS 1 mutations, and to neurons in the PS / APP mouse model of AD . Autophagy is a process to recycle cellular waste that relies on correct functioning of the lysosome. The complex regulation of lysosomal pH makes this process vulnerable to disruption by many factors and reliable lysosomal pH measurements are increasingly important in investigations of disease mechanisms. Here we evaluate the most commonly used pH probes and review evidence that lysosomal acidification is defective in Alzheimer's disease (AD), extending our original findings of elevated lysosomal pH in presenilin 1 knockout cells.
The P300 component of the human event‐related potential has been the subject of intensive experimental investigation across a five‐decade period, owing to its apparent relevance to a wide range of cognitive functions and its sensitivity to numerous brain disorders, yet its exact contribution to cognition remains unresolved. Here, we carry out key analyses of the P300 elicited by transient auditory and visual targets to examine its potential role as a ‘decision variable’ signal that accumulates evidence to a decision bound. Consistent with the latter, we find that the P300 reaches a stereotyped amplitude immediately prior to response execution and that its rate of rise scales with target detection difficulty and accounts for trial‐to‐trial variance in RT . Computational simulations of an accumulation‐to‐bound decision process faithfully captured P300 dynamics when its parameters were set by model fits to the RT distributions. Thus, where the dominant explanatory accounts have conceived of the P300 as a unitary neural event, our data reveal it to be a dynamically evolving neural signature of decision formation. These findings place the P300 at the heart of a mechanistically principled framework for understanding decision‐making in both the typical and atypical human brain. The P300 potential continually draws widespread interest in basic and clinical neuroscience, yet its functional significance has never been established. Through novel analyses of buildup and peak dynamics along with computational simulations, Twomey et al . show that it reflects a decision formation process that accumulates evidence to a threshold.
The generation and cell death of newly generated cells have critical roles in brain development and maintenance in the embryonic and adult brain. Alterations in these processes are also seen in neurodegenerative diseases. Genes that are key players in neurodegenerative diseases (α‐synuclein, presenilin‐1, tau, huntingtin) are also physiologically involved in modulating brain plasticity. Interestingly, in some neurodegenerative diseases, the specific alterations in neurogenic areas such as the dentate gyrus and subventricular zone/olfactory bulb system parallel the early or premotor symptoms that are seen in the early stages of these diseases, such as depression, anxiety or olfactory dysfunction. We will review the modulation of neurogenesis in animal models and human brains of Parkinson’s disease, Huntington’s disease and Alzheimer’s disease.
NMDA receptors (NMDARs) form glutamate‐gated ion channels widely expressed in the central nervous system and highly permeable to calcium ions. NMDARs have always attracted much attention because of their central implications in numerous physiological and pathological processes including synaptic plasticity and excitotoxicity. Ever since the discovery of NMDARs three decades ago, it has been acknowledged that native NMDARs do not form a homogeneous population of receptors but rather exist as multiple subpopulations that differ in their functional properties and, presumably, physiopathological roles. NMDARs are in fact large multi‐subunit complexes arranged into heteromeric assemblies composed of four homologous subunits within a repertoire of over 10 different subunits: eight GluN1 isoforms, four GluN2 subunits (A–D) and two GluN3 subunits (A and B). This review gives an overview of our current knowledge of the molecular basis underlying NMDAR functional heterogeneity. The modular architecture and expression profile of NMDAR subunits together with the basic principles of NMDAR operation are first introduced. The influence of subunit composition on receptor functional properties is then described, with emphasis put on the impact of differential incorporation of GluN1 and GluN2 subunits (the roles of GluN3 subunits being less well understood). The final part presents recent studies revealing the central, and largely unsuspected, role of the extracellular N‐terminal region in generating functional diversity of NMDARs. Indeed, the identity of this region, which is distal to the membrane and precedes the agonist‐binding domains, determines key biophysical and pharmacological attributes of the various NMDAR subtypes.
Habits are characterized by an insensitivity to their consequences and, as such, can be distinguished from goal-directed actions. The neural basis of the development of demonstrably outcome-insensitive habitual actions in humans has not been previously characterized. In this experiment, we show that extensive training on a free-operant task reduces the sensitivity of participants' behavior to a reduction in outcome value. Analysis of functional magnetic resonance imaging data acquired during training revealed a significant increase in task-related cue sensitivity in a right posterior putamen-globus pallidus region as training progressed. These results provide evidence for a shift from goal-directed to habit-based control of instrumental actions in humans, and suggest that cue-driven activation in a specific region of dorsolateral posterior putamen may contribute to the habitual control of behavior in humans.
Fear extinction is a form of inhibitory learning that allows for the adaptive control of conditioned fear responses. Although fear extinction is an active learning process that eventually leads to the formation of a consolidated extinction memory, it is a fragile behavioural state. Fear responses can recover spontaneously or subsequent to environmental influences, such as context changes or stress. Understanding the neuronal substrates of fear extinction is of tremendous clinical relevance, as extinction is the cornerstone of psychological therapy of several anxiety disorders and because the relapse of maladaptative fear and anxiety is a major clinical problem. Recent research has begun to shed light on the molecular and cellular processes underlying fear extinction. In particular, the acquisition, consolidation and expression of extinction memories are thought to be mediated by highly specific neuronal circuits embedded in a large-scale brain network including the amygdala, prefrontal cortex, hippocampus and brain stem. Moreover, recent findings indicate that the neuronal circuitry of extinction is developmentally regulated. Here, we review emerging concepts of the neuronal circuitry of fear extinction, and highlight novel findings suggesting that the fragile phenomenon of extinction can be converted into a permanent erasure of fear memories. Finally, we discuss how research on genetic animal models of impaired extinction can further our understanding of the molecular and genetic bases of human anxiety disorders.
The role of dopamine in reward is a topic of debate. For example, some have argued that phasic dopamine signaling provides a prediction‐error signal necessary for stimulus–reward learning, whereas others have hypothesized that dopamine is not necessary for learning per se , but for attributing incentive motivational value (‘incentive salience’) to reward cues. These psychological processes are difficult to tease apart, because they tend to change together. To disentangle them we took advantage of natural individual variation in the extent to which reward cues are attributed with incentive salience, and asked whether dopamine (specifically in the core of the nucleus accumbens) is necessary for the expression of two forms of Pavlovian‐conditioned approach behavior – one in which the cue acquires powerful motivational properties (sign‐tracking) and another closely related one in which it does not (goal‐tracking). After acquisition of these conditioned responses (CRs), intra‐accumbens injection of the dopamine receptor antagonist flupenthixol markedly impaired the expression of a sign‐tracking CR, but not a goal‐tracking CR. Furthermore, dopamine antagonism did not produce a gradual extinction‐like decline in behavior, but maximally impaired expression of a sign‐tracking CR on the very first trial, indicating the effect was not due to new learning (i.e. it occurred in the absence of new prediction‐error computations). The data support the view that dopamine in the accumbens core is not necessary for learning stimulus–reward associations, but for attributing incentive salience to reward cues, transforming predictive conditional stimuli into incentive stimuli with powerful motivational properties. Ongoing debate exists about dopamine’s exact role in reward‐related processes. We took advantage of natural individual variation in the degree to which reward cues are attributed with motivational value, and asked whether dopamine in the core of the nucleus accumbens is necessary for the performance of two forms of Pavlovian conditioned approach behavior ‐ one in which the cue acquires powerful motivational properties (sign‐tracking) and another related one in which it does not (goal‐tracking). We found that blocking dopamine transmission within the core impaired the expression of sign‐tracking responses, but not goal‐tracking responses.
In primary sensory neocortical areas of mammals, the distribution of sensory receptors is mapped with topographic precision and amplification in proportion to the peripheral receptor density. The visual, somatosensory and auditory cortical maps are established during a critical period in development. Throughout this window in time, the developing cortical maps are vulnerable to deleterious effects of sense organ damage or sensory deprivation. The rodent barrel cortex offers an invaluable model system with which to investigate the mechanisms underlying the formation of topographic maps and their plasticity during development. Five rows of mystacial vibrissa (whisker) follicles on the snout and an array of sinus hairs are represented by layer IV neural modules (‘barrels’) and thalamocortical axon terminals in the primary somatosensory cortex. Perinatal damage to the whiskers or the sensory nerve innervating them irreversibly alters the structural organization of the barrels. Earlier studies emphasized the role of the sensory periphery in dictating whisker‐specific brain maps and patterns. Recent advances in molecular genetics and analyses of genetically altered mice allow new insights into neural pattern formation in the neocortex and the mechanisms underlying critical period plasticity. Here, we review the development and patterning of the barrel cortex and the critical period plasticity. Schematic diagram illustrating the classical structural plasticity in the barrel cortex following row C whisker lesions or infraorbital nerve transection. These effects are only seen when peripheral lesions are performed up to postnatal day 3. The patterns and deficits are routinely assessed by histochemical stains such as succinic dehydrogenase or cytochrome oxidase histochemistry or with immunohistochemistry for TCA markers such as 5‐HTT or vesicular glutamate transporter 2 or by Nissl or Golgi stains for neuronal and dendritic organization.
The neurogenesis hypothesis of depression was originally formed upon the demonstration that stress impacts levels of adult neurogenesis in the hippocampus. Since then much work has established that newborn neurons in the dentate gyrus are required for mediating some of the beneficial effects of antidepressant treatment. Recent studies combining behavioral, molecular and electrophysiological approaches have attempted to make sense of the role young neurons play in modulating mood by demonstrating a potential role in regulating the circuitry in the brain that underlies depression. Here we discuss the work that led to the neurogenesis hypothesis of depression, and the subsequent studies that have sought to test this hypothesis. We also discuss different animal models of depression that have been used to test the role of neurogenesis in mediating the antidepressant response.
Increasing evidence implicates the microbiota in the regulation of brain and behaviour. Germ‐free mice ( GF ; microbiota deficient from birth) exhibit altered stress hormone signalling and anxiety‐like behaviours as well as deficits in social cognition. Although the mechanisms underlying the ability of the gut microbiota to influence stress responsivity and behaviour remain unknown, many lines of evidence point to the amygdala and hippocampus as likely targets. Thus, the aim of this study was to determine if the volume and dendritic morphology of the amygdala and hippocampus differ in GF versus conventionally colonized ( CC ) mice. Volumetric estimates revealed significant amygdalar and hippocampal expansion in GF compared to CC mice. We also studied the effect of GF status on the level of single neurons in the basolateral amygdala ( BLA ) and ventral hippocampus. In the BLA , the aspiny interneurons and pyramidal neurons of GF mice exhibited dendritic hypertrophy. The BLA pyramidal neurons of GF mice had more thin, stubby and mushroom spines. In contrast, the ventral hippocampal pyramidal neurons of GF mice were shorter, less branched and had less stubby and mushroom spines. When compared to controls, dentate granule cells of GF mice were less branched but did not differ in spine density. These findings suggest that the microbiota is required for the normal gross morphology and ultrastructure of the amygdala and hippocampus and that this neural remodelling may contribute to the maladaptive stress responsivity and behavioural profile observed in GF mice. Germ‐free mice (GF; microbiota deficient from birth) exhibit alterations in stress responsivity, anxiety‐like behaviour, and sociability, effects influenced by the amygdala and hippocampus. Here, we show that there are alterations in the gross morphology and ultrastructure of the amygdala and hippocampus of GF mice. These findings indicate that the microbiota is required for normal brain structure and that these neuronal changes may contribute to the maladaptive behavioural profile of GF mice.
This review charts recent advances from a variety of disciplines that create a new perspective on why the multiple hippocampal-anterior thalamic interconnections are together vital for human episodic memory and rodent event memory. Evidence has emerged for the existence of a series of parallel temporal-diencephalic pathways that function in a reciprocal manner, both directly and indirectly, between the hippocampal formation and the anterior thalamic nuclei. These extended pathways also involve the mammillary bodies, the retrosplenial cortex and parts of the prefrontal cortex. Recent neuropsychological findings reveal the disproportionate importance of these hippocampal-anterior thalamic systems for recollective rather than familiarity-based recognition, while anatomical studies highlight the precise manner in which information streams are kept separate but can also converge at key points within these pathways. These latter findings are developed further by electrophysiological stimulation studies showing how the properties of the direct hippocampal-anterior thalamic projections are often opposed by the indirect hippocampal projections via the mammillary bodies to the thalamus. Just as these hippocampal-anterior thalamic interactions reflect an interdependent system, so it is also the case that pathology in one of the component sites within this system can induce dysfunctional changes to distal sites both directly and indirectly across the system. Such distal effects challenge more traditional views of neuropathology as they reveal how extensive covert pathology might accompany localised overt pathology, and so impair memory.
GABA A receptors ( GABA A R s) are ligand‐gated Cl − channels that mediate most of the fast inhibitory neurotransmission in the central nervous system ( CNS ). Multiple GABA A R subtypes are assembled from a family of 19 subunit genes, raising the question of the significance of this heterogeneity. In this review, we discuss the evidence that GABA A R subtypes represent distinct receptor populations with a specific spatio‐temporal expression pattern in the developing and adult CNS , being endowed with unique functional and pharmacological properties, as well as being differentially regulated at the transcriptional, post‐transcriptional and translational levels. GABA A R subtypes are targeted to specific subcellular domains to mediate either synaptic or extrasynaptic transmission, and their action is dynamically regulated by a vast array of molecular mechanisms to adjust the strength of inhibition to the changing needs of neuronal networks. These adaptations involve not only changing the gating or kinetic properties of GABA A R s, but also modifying the postsynaptic scaffold organised by gephyrin to anchor specific receptor subtypes at postsynaptic sites. The significance of GABA A R heterogeneity is particularly evident during CNS development and adult neurogenesis, with different receptor subtypes fulfilling distinct steps of neuronal differentiation and maturation. Finally, analysis of the specific roles of GABA A R subtypes reveals their involvement in the pathophysiology of major CNS disorders, and opens novel perspectives for therapeutic intervention. In conclusion, GABA A R subtypes represent the substrate of a multifaceted inhibitory neurotransmission system that is dynamically regulated and performs multiple operations, contributing globally to the proper development, function and plasticity of the CNS . GABA A receptor heterogeneity arises through combinatorial assembly of a large family of subunits to generate multiple receptor subtypes. It is an important facet of the variety of GABAergic signaling in adult and developing CNS, and a key factor underlying GABAergic synaptic plasticity underlying excitatory/inhibitory balance in neuronal circuits. This review presents and discusses recent progress in elucidating the relevance of GABA A receptor heterogeneity for CNS function in health and disease.
The present quantitative meta‐analysis set out to test whether cue‐reactivity responses in humans differ across drugs of abuse and whether these responses constitute the biological basis of drug craving as a core psychopathology of addiction. By means of activation likelihood estimation, we investigated the concurrence of brain regions activated by cue‐induced craving paradigms across studies on nicotine, alcohol and cocaine addicts. Furthermore, we analysed the concurrence of brain regions positively correlated with self‐reported craving in nicotine and alcohol studies. We found direct overlap between nicotine, alcohol and cocaine cue reactivity in the ventral striatum. In addition, regions of close proximity were observed in the anterior cingulate cortex (ACC; nicotine and cocaine) and amygdala (alcohol, nicotine and cocaine). Brain regions of concurrence in drug cue‐reactivity paradigms that overlapped with brain regions of concurrence in self‐reported craving correlations were found in the ACC, ventral striatum and right pallidum (for alcohol). This first quantitative meta‐analysis on drug cue reactivity identifies brain regions underlying nicotine, alcohol and cocaine dependency, i.e. the ventral striatum. The ACC, right pallidum and ventral striatum were related to drug cue reactivity as well as self‐reported craving, suggesting that this set of brain regions constitutes the core circuit of drug craving in nicotine and alcohol addiction.
The pedunculopontine tegmental nucleus (PPTg) and laterodorsal tegmental nucleus (LDTg) provide cholinergic afferents to several brain areas. This cholinergic complex has been suggested to play a role in sleep, waking, motor function, learning and reward. To have a better understanding of the neurochemical organization of the PPTg/LDTg we characterized the phenotype of PPTg/LDTg neurons by determining in these cells the expression of transcripts encoding choline acetyltransferase (ChAT), glutamic acid decarboxylase (GAD) or the vesicular glutamate transporters (vGluT1, vGluT2 and vGluT3). Within the PPTg/LDTg complex we found neurons expressing ChAT, vGluT2 or GAD transcripts, these neuronal phenotypes were intermingled, but not homogeneously distributed within the PPTg or LDTg. Previous studies suggested the presence of either glutamate or gamma-aminobutyric acid (GABA) immunolabeling in a large number of PPTg/LDTg cholinergic neurons, leading to the widespread notion that PPTg/LDTg cholinergic neurons co-release acetylcholine together with either glutamate or GABA. To assess the glutamatergic or GABAergic nature of the PPTg/LDTg cholinergic neurons, we combined in situ hybridization (to detect vGluT2 or GAD transcripts) and immunohistochemistry (to detect ChAT), and found that over 95% of all PPTg/LDTg cholinergic neurons lack transcripts encoding either vGluT2 mRNA or GAD mRNA. As the vast majority of PPTg/LDTg cholinergic neurons lack transcripts encoding essential proteins for the vesicular transport of glutamate or for the synthesis of GABA, co-release of acetylcholine with either glutamate or GABA is unlikely to be a major factor in the interactions between acetylcholine, glutamate and GABA at the postsynaptic site.
We have evaluated the possibility that the action of voluntary exercise on the regulation of brain‐derived neurotrophic factor (BDNF), a molecule important for rat hippocampal learning, could involve mechanisms of epigenetic regulation. We focused the studies on the Bdnf promoter IV, as this region is highly responsive to neuronal activity. We have found that exercise stimulates DNA demethylation in Bdnf promoter IV, and elevates levels of activated methyl‐CpG‐binding protein 2, as well as BDNF mRNA and protein in the rat hippocampus. Chromatin immunoprecipitation assay showed that exercise increases acetylation of histone H3, and protein assessment showed that exercise elevates the ratio of acetylated : total for histone H3 but had no effects on histone H4 levels. Exercise also reduces levels of the histone deacetylase 5 mRNA and protein implicated in the regulation of the Bdnf gene [N.M. Tsankova (2006) Nat. Neurosci. , 9 , 519–525], but did not affect histone deacetylase 9. Exercise elevated the phosphorylated forms of calcium/calmodulin‐dependent protein kinase II and cAMP response element binding protein, implicated in the pathways by which neural activity influences the epigenetic regulation of gene transcription, i.e. Bdnf . These results showing the influence of exercise on the remodeling of chromatin containing the Bdnf gene emphasize the importance of exercise on the control of gene transcription in the context of brain function and plasticity. Reported information about the impact of a behavior, inherently involved in the daily human routine, on the epigenome opens exciting new directions and therapeutic opportunities in the war against neurological and psychiatric disorders.
Here we challenge the view that reward-guided learning is solely controlled by the mesoaccumbens pathway arising from dopaminergic neurons in the ventral tegmental area and projecting to the nucleus accumbens. This widely accepted view assumes that reward is a monolithic concept, but recent work has suggested otherwise. It now appears that, in reward-guided learning, the functions of ventral and dorsal striata, and the cortico-basal ganglia circuitry associated with them, can be dissociated. Whereas the nucleus accumbens is necessary for the acquisition and expression of certain appetitive Pavlovian responses and contributes to the motivational control of instrumental performance, the dorsal striatum is necessary for the acquisition and expression of instrumental actions. Such findings suggest the existence of multiple independent yet interacting functional systems that are implemented in iterating and hierarchically organized cortico-basal ganglia networks engaged in appetitive behaviors ranging from Pavlovian approach responses to goal-directed instrumental actions controlled by action-outcome contingencies.