Showing papers in "European Journal of Neuroscience in 2012"

From prediction error to incentive salience: mesolimbic computation of reward motivation.

Abstract: 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.

How much of reinforcement learning is working memory, not reinforcement learning? A behavioral, computational, and neurogenetic analysis

Abstract: Instrumental learning involves corticostriatal circuitry and the dopaminergic system. This system is typically modeled in the reinforcement learning (RL) framework by incrementally accumulating reward values of states and actions. However, human learning also implicates prefrontal cortical mechanisms involved in higher level cognitive functions. The interaction of these systems remains poorly understood, and models of human behavior often ignore working memory (WM) and therefore incorrectly assign behavioral variance to the RL system. Here we designed a task that highlights the profound entanglement of these two processes, even in simple learning problems. By systematically varying the size of the learning problem and delay between stimulus repetitions, we separately extracted WM-specific effects of load and delay on learning. We propose a new computational model that accounts for the dynamic integration of RL and WM processes observed in subjects' behavior. Incorporating capacity-limited WM into the model allowed us to capture behavioral variance that could not be captured in a pure RL framework even if we (implausibly) allowed separate RL systems for each set size. The WM component also allowed for a more reasonable estimation of a single RL process. Finally, we report effects of two genetic polymorphisms having relative specificity for prefrontal and basal ganglia functions. Whereas the COMT gene coding for catechol-O-methyl transferase selectively influenced model estimates of WM capacity, the GPR6 gene coding for G-protein-coupled receptor 6 influenced the RL learning rate. Thus, this study allowed us to specify distinct influences of the high-level and low-level cognitive functions on instrumental learning, beyond the possibilities offered by simple RL models.

The role of dopamine in the accumbens core in the expression of Pavlovian conditioned responses

Abstract: 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 (goaltracking). 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.

Development and Critical Period Plasticity of the Barrel Cortex

Abstract: 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.

Habits, action sequences and reinforcement learning

Abstract: It is now widely accepted that instrumental actions can be either goal-directed or habitual; whereas the former are rapidly acquired and regulated by their outcome, the latter are reflexive, elicited by antecedent stimuli rather than their consequences. Model-based reinforcement learning (RL) provides an elegant description of goal-directed action. Through exposure to states, actions and rewards, the agent rapidly constructs a model of the world and can choose an appropriate action based on quite abstract changes in environmental and evaluative demands. This model is powerful but has a problem explaining the development of habitual actions. To account for habits, theorists have argued that another action controller is required, called model-free RL, that does not form a model of the world but rather caches action values within states allowing a state to select an action based on its reward history rather than its consequences. Nevertheless, there are persistent problems with important predictions from the model; most notably the failure of model-free RL correctly to predict the insensitivity of habitual actions to changes in the action-reward contingency. Here, we suggest that introducing model-free RL in instrumental conditioning is unnecessary, and demonstrate that reconceptualizing habits as action sequences allows model-based RL to be applied to both goal-directed and habitual actions in a manner consistent with what real animals do. This approach has significant implications for the way habits are currently investigated and generates new experimental predictions.

Touching and feeling: differences in pleasant touch processing between glabrous and hairy skin in humans

Abstract: Previous functional magnetic resonance imaging studies in two rare patients, together with microneurography and psychophysical observations in healthy subjects, have demonstrated a system of mechanosensitive C-fiber tactile (CT) afferents sensitive to slowly moving stimuli. They project to the posterior insular cortex and signal pleasant aspects of touch. Importantly, CTs have not been found in the glabrous skin of the hand, yet it is commonly observed that glabrous skin touch is also perceived as pleasant. Here we asked if the brain processing of pleasant touch differs between hairy and glabrous skin by stroking the forearm and glabrous skin of the hand during positron emission tomography. The data showed that, when contrasting slow brush stroking on the forearm with slow brush stroking on the palm, there were significant activations of the posterior insular cortex and mid-anterior orbitofrontal cortex. The opposite contrast showed a significant activation of the somatosensory cortices. Although concurrent psychophysical ratings showed no differences in intensity or pleasantness ratings, a subsequent touch questionnaire in which subjects used a newly developed 'touch perception task' showed significant difference for the two body sites. Emotional descriptors received higher ratings on the forearm and sensory descriptors were rated more highly on the palm. The present findings are consistent with the hypothesis that pleasant touch from hairy skin, mediated by CT afferents, is processed in the limbic-related cortex and represents an innate non-learned process. In contrast, pleasant touch from glabrous skin, mediated by A-beta afferents, is processed in the somatosensory cortex and represents an analytical process dependent on previous tactile experiences.

At what time is the cocktail party? A late locus of selective attention to natural speech.

Abstract: Distinguishing between speakers and focusing attention on one speaker in multi-speaker environments is extremely important in everyday life. Exactly how the brain accomplishes this feat and, in particular, the precise temporal dynamics of this attentional deployment are as yet unknown. A long history of behavioral research using dichotic listening paradigms has debated whether selective attention to speech operates at an early stage of processing based on the physical characteristics of the stimulus or at a later stage during semantic processing. With its poor temporal resolution fMRI has contributed little to the debate, while EEG–ERP paradigms have been hampered by the need to average the EEG in response to discrete stimuli which are superimposed onto ongoing speech. This presents a number of problems, foremost among which is that early attention effects in the form of endogenously generated potentials can be so temporally broad as to mask later attention effects based on the higher level processing of the speech stream. Here we overcome this issue by utilizing the AESPA (auditory evoked spread spectrum analysis) method which allows us to extract temporally detailed responses to two concurrently presented speech streams in natural cocktailparty-like attentional conditions without the need for superimposed probes. We show attentional effects on exogenous stimulus processing in the 200–220 ms range in the left hemisphere. We discuss these effects within the context of research on auditory scene analysis and in terms of a flexible locus of attention that can be deployed at a particular processing stage depending on the task.

Insulin in the ventral tegmental area reduces hedonic feeding and suppresses dopamine concentration via increased reuptake.

Abstract: Mesolimbic dopamine (DA) signaling has been implicated in the incentive, reinforcing and motivational aspects of food intake. Insulin receptors are expressed on dopaminergic neurons of the ventral tegmental area (VTA), and insulin may act in the VTA to suppress feeding. However, the neural mechanisms underlying insulin effects in the VTA are poorly understood. Here, we measured the effects of insulin on evoked DA concentration in the VTA using fast-scan cyclic voltammetry. Insulin concentration-dependently reduced evoked somatodendritic DA in the VTA, requiring activation of phosphoinositol 3-kinase and mTOR signaling. Insulin depression of somatodendritic DA was abolished in the presence of a selective DA transporter (DAT) inhibitor, GBR 12909, as well as in VTA slices of DAT knockout mice, suggesting that insulin upregulated the number or function of DAT to reduce DA concentration. Finally, insulin administered to the VTA depressed sated feeding of sweetened high-fat food. Taken together, these results indicate that insulin depresses DA concentration in the VTA via increased reuptake of DA through DAT. Insulin-mediated decrease of DA in the VTA may suppress salience of food once satiety is reached.

Surprise! Neural correlates of Pearce-Hall and Rescorla-Wagner coexist within the brain.

Abstract: Learning theory and computational accounts suggest that learning depends on errors in outcome prediction as well as changes in processing of or attention to events. These divergent ideas are captured by models, such as Rescorla-Wagner (RW) and temporal difference (TD) learning on the one hand, which emphasize errors as directly driving changes in associative strength, vs. models such as Pearce-Hall (PH) and more recent variants on the other hand, which propose that errors promote changes in associative strength by modulating attention and processing of events. Numerous studies have shown that phasic firing of midbrain dopamine (DA) neurons carries a signed error signal consistent with RW or TD learning theories, and recently we have shown that this signal can be dissociated from attentional correlates in the basolateral amygdala and anterior cingulate. Here we will review these data along with new evidence: (i) implicating habenula and striatal regions in supporting error signaling in midbrain DA neurons; and (ii) suggesting that the central nucleus of the amygdala and prefrontal regions process the amygdalar attentional signal. However, while the neural instantiations of the RW and PH signals are dissociable and complementary, they may be linked. Any linkage would have implications for understanding why one signal dominates learning in some situations and not others, and also for appreciating the potential impact on learning of neuropathological conditions involving altered DA or amygdalar function, such as schizophrenia, addiction or anxiety disorders.

A Goal-Directed Spatial Navigation Model Using Forward Trajectory Planning Based on Grid Cells

Abstract: A goal-directed navigation model is proposed based on forward linear look-ahead probe of trajectories in a network of head direction cells, grid cells, place cells and prefrontal cortex (PFC) cells. The model allows selection of new goal-directed trajectories. In a novel environment, the virtual rat incrementally creates a map composed of place cells and PFC cells by random exploration. After exploration, the rat retrieves memory of the goal location, picks its next movement direction by forward linear look-ahead probe of trajectories in several candidate directions while stationary in one location, and finds the one activating PFC cells with the highest reward signal. Each probe direction involves activation of a static pattern of head direction cells to drive an interference model of grid cells to update their phases in a specific direction. The updating of grid cell spiking drives place cells along the probed look-ahead trajectory similar to the forward replay during waking seen in place cell recordings. Directions are probed until the look-ahead trajectory activates the reward signal and the corresponding direction is used to guide goal-finding behavior. We report simulation results in several mazes with and without barriers. Navigation with barriers requires a PFC map topology based on the temporal vicinity of visited place cells and a reward signal diffusion process. The interaction of the forward linear look-ahead trajectory probes with the reward diffusion allows discovery of never-before experienced shortcuts towards a goal location.

Re‐evaluating the role of the orbitofrontal cortex in reward and reinforcement

Abstract: The orbitofrontal cortex and adjacent ventromedial prefrontal cortex carry reward representations and mediate flexible behaviour when circumstances change. Here we review how recent experiments in humans and macaques have confirmed the existence of a major difference between the functions of the ventromedial prefrontal cortex and adjacent medial orbitofrontal cortex (mOFC) on the one hand and the lateral orbitofrontal cortex (lOFC) on the other. These differences, however, may not be best accounted for in terms of specializations for reward and error/punishment processing as is commonly assumed. Instead we argue that both lesion and functional magnetic resonance imaging studies reveal that the lOFC is concerned with the assignment of credit for both reward and error outcomes to the choice of specific stimuli and with the linking of specific stimulus representations to representations of specific types of reward outcome. By contrast, we argue that the ventromedial prefrontal cortex/mOFC is concerned with evaluation, value-guided decision-making and maintenance of a choice over successive decisions. Despite the popular view that they cause perseveration of behaviour and inability to inhibit repetition of a previously made choice, we found that lesions in neither orbitofrontal subdivision caused perseveration. On the contrary, lesions in the lOFC made animals switch more rapidly between choices when they were finding it difficult to assign reward values to choices. Lesions in the mOFC caused animals to lose their normal predisposition to repeat previously successful choices, suggesting that the mOFC does not just mediate value comparison in choice but also facilitates maintenance of the same choice if it has been successful.

Exploration and Modulation of Brain Network Interactions with Noninvasive Brain Stimulation in Combination with Neuroimaging

Abstract: Much recent work in systems neuroscience has focused on how dynamic interactions between different cortical regions underlie complex brain functions such as motor coordination, language and emotional regulation. Various studies using neuroimaging and neurophysiologic techniques have suggested that in many neuropsychiatric disorders, these dynamic brain networks are dysregulated. Here we review the utility of combined noninvasive brain stimulation and neuroimaging approaches towards greater understanding of dynamic brain networks in health and disease. Brain stimulation techniques, such as transcranial magnetic stimulation and transcranial direct current stimulation, use electromagnetic principles to alter brain activity noninvasively, and induce focal but also network effects beyond the stimulation site. When combined with brain imaging techniques such as functional magnetic resonance imaging, positron emission tomography and electroencephalography, these brain stimulation techniques enable a causal assessment of the interaction between different network components, and their respective functional roles. The same techniques can also be applied to explore hypotheses regarding the changes in functional connectivity that occur during task performance and in various disease states such as stroke, depression and schizophrenia. Finally, in diseases characterized by pathologic alterations in either the excitability within a single region or in the activity of distributed networks, such techniques provide a potential mechanism to alter cortical network function and architectures in a beneficial manner.

How many neurons do you have? Some dogmas of quantitative neuroscience under revision.

Abstract: Owing to methodological shortcomings and a certain conservatism that consolidates wrong assumptions in the literature, some dogmas have become established and reproduced in papers and textbooks, derived from quantitative features of the brain. The first dogma states that the cerebral cortex is the pinnacle of brain evolution – based on the observations that its volume is greater in more ‘intelligent’ species, and that cortical surface area grows more than any other brain region, to reach the largest proportion in higher primates and humans. The second dogma claims that the human brain contains 100 billion neurons, plus 10-fold more glial cells. These round numbers have become widely adopted, although data provided by different authors have led to a broad range of 75–125 billion neurons in the whole brain. The third dogma derives from the second, and states that our brain is structurally special, an outlier as compared with other primates. Being so large and convoluted, it is a special construct of nature, unrelated to evolutionary scaling. Finally, the fourth dogma appeared as a tentative explanation for the considerable growth of the brain throughout development and evolution – being modular in structure, the brain (and particularly the cerebral cortex) grows by tangential addition of modules that are uniform in neuronal composition. In this review, we sought to examine and challenge these four dogmas, and propose other interpretations or simply their replacement with alternative views.

Projections and interconnections of genetically defined serotonin neurons in mice.

Abstract: Brain serotonin neurons are heterogeneous and can be distinguished by several anatomical and physiological characteristics. Toward resolving this heterogeneity into classes of functional relevance, subtypes of mature serotonin neurons were previously identified based on gene expression differences initiated during development in different rhombomeric (r) segments of the hindbrain. This redefinition of mature serotonin neuron subtypes based on the criteria of genetic lineage, along with the enabling genetic fate mapping tools, now allows various functional properties, such as axonal projections, to be allocated onto these identified subtypes. Furthermore, our approach uniquely enables interconnections between the different serotonin neuron subtypes to be determined; this is especially relevant because serotonin neuron activity is regulated by several feedback mechanisms. We used intersectional and subtractive genetic fate mapping tools to generate three independent lines of mice in which serotonin neurons arising in different rhombomeric segments, either r1, r2 or both r3 and r5, were uniquely distinguished from all other serotonin neurons by their expression of enhanced green fluorescent protein. Each of these subgroups of serotonergic neurons had a unique combination of forebrain projection targets. Typically more than one subgroup innervated an individual target area. Unique patterns of interconnections between the different groups of serotonin neurons were also observed and these pathways could subserve feedback regulatory circuits. Overall, the current findings suggest that activation of subsets of serotonin neurons could result in topographic serotonin release in the forebrain coupled with feedback inhibition of serotonin neurons with alternative projection targets.

Unveiling the diversity of thalamocortical neuron subtypes.

Abstract: Our current understanding of thalamocortical (TC) circuits is largely based on studies investigating so-called 'specific' thalamic nuclei, which receive and transmit sensory-triggered input to specific cortical target areas. TC neurons in these nuclei have a striking point-to-point topography and a stereotyped laminar pattern of termination in the cortex, which has made them ideal models to study the organization, plasticity, and development of TC circuits. However, despite their experimental importance, neurons within these nuclei only represent a fraction of all thalamic neurons and do not reflect the diversity of the TC neuron population. Here we review the distinct subtypes of projection neurons that populate the thalamus, both within and across anatomically-defined nuclei, with regard to differences in their morphology, input/output connectivity and target specificity, as well as more recent findings on their neuron type-specific gene expression and development. We argue that a detailed understanding of the biology of TC neurons is critical to understand the role of the thalamus in normal and pathological perception, voluntary movement, cognition and attention.

Neural circuit competition in cocaine-seeking: roles of the infralimbic cortex and nucleus accumbens shell

Abstract: Following cocaine self-administration and extinction training, activity in the infralimbic cortex (IL) suppresses cocaine-seeking behavior. IL inactivation induces cocaine-seeking whereas activation suppresses cocaine-reinstated drug-seeking. We asked how the suppression of cocaine-seeking induced by IL activation integrates with the circuitry promoting reinstated cocaine-seeking. Following cocaine self-administration and extinction training, rats underwent cue-induced reinstatement. In order to activate IL projections, microinjections of PEPA, a positive allosteric modulator of AMPA receptors, were made into the IL in combination with microinjections into a variety of nuclei known to regulate cocaine-seeking. Intra-IL PEPA administration suppressed cue-induced reinstatement without affecting locomotor activity. The suppression of cocaine-seeking was reversed by activating dopamine neurons in the ventral tegmental area with microinjections of the μ-opioid receptor agonist DAMGO, and was partially reversed by dopamine microinjections into the prelimbic cortex or basolateral amygdala. Previous evidence suggests that the nucleus accumbens shell both promotes and suppresses cocaine-seeking. The suppression of cue-induced cocaine seeking by PEPA in the IL was reversed by intra-shell microinjections of either dopamine or the AMPA receptor antagonist CNQX, suggesting that the accumbens shell bidirectionally regulates cocaine-seeking depending on whether dopamine input is mimicked or glutamate input is inhibited. Together, these findings indicate that the IL acts 'upstream' from structures promoting cocaine-seeking, including from the mesolimbic dopamine projections to the prelimbic cortex and basolateral amygdala, and that the accumbens shell may be a crucial point of integration between the circuits that promote (ventral tegmental area) and inhibit (IL) reinstated cocaine-seeking.

The application of spaced theta burst protocols induces long-lasting neuroplastic changes in the human motor cortex

Abstract: There is some limited evidence suggesting that the spaced application of repetitive transcranial magnetic stimulation (rTMS) protocols may extend the duration of induced neuroplastic changes However, this has yet to be demonstrated in the human primary motor cortex (M1) We evaluated whether the paired application of an inhibitory rTMS protocol [continuous theta burst stimulation (cTBS)] at 10-min intervals prolonged the duration of induced M1 plasticity Motor evoked potentials (MEPs) were recorded from the right first dorsal interosseous muscle before and following single and paired cTBS protocols applied with two intensities: 80% of active motor threshold (AMT(80)) and 70% of resting motor threshold (RMT(70)) Single cTBS protocols did not significantly influence MEP amplitudes Whereas paired trains applied at AMT(80) had no effect on MEP amplitudes, paired cTBS trains at RMT(70) significantly reduced them MEP amplitudes remained suppressed for at least 2 h following the second train Control experiments suggested that the contraction used to establish active motor threshold prior to cTBS application may be responsible for blocking the effect of paired cTBS trains at AMT(80) The results suggest that the spaced application of cTBS protocols may be an effective approach for establishing long-lasting M1 neuroplasticity only in the absence of prior voluntary motor activation These findings may have important implications for the therapeutic application of rTMS

Action anticipation beyond the action observation network: a functional magnetic resonance imaging study in expert basketball players.

Abstract: The ability to predict the actions of others is quintessential for effective social interactions, particularly in competitive contexts (e.g. in sport) when knowledge about upcoming movements allows anticipating rather than reacting to opponents. Studies suggest that we predict what others are doing by using our own motor system as an internal forward model and that the fronto-parietal action observation network (AON) is fundamental for this ability. However, multiple-duty cells dealing with action perception and execution have been found in a variety of cortical regions. Here we used functional magnetic resonance imaging to explore, in expert basketball athletes and novices, whether the ability to make early predictions about the fate of sport-specific actions (i.e. free throws) is underpinned by neural regions beyond the classical AON. We found that, although involved in action prediction, the fronto-parietal AON was similarly activated in novices and experts. Importantly, athletes exhibited relatively greater activity in the extrastriate body area during the prediction task, probably due to their expert reading of the observed action kinematics. Moreover, experts exhibited higher activation in the bilateral inferior frontal gyrus and in the right anterior insular cortex when producing errors, suggesting that they might become aware of their own errors. Correct action prediction induced higher posterior insular cortex activity in experts and higher orbito-frontal activity in novices, suggesting that body awareness is important for performance monitoring in experts, whereas novices rely more on higher-order decision-making strategies. This functional reorganization highlights the tight relationship between action anticipation, error awareness and motor expertise leading to body-related processing and differences in decision-making processes.

AMPA receptors as drug targets in neurological disease--advantages, caveats, and future outlook

Abstract: Most excitatory transmission in the brain is mediated by the AMPA receptor subtype of the ionotropic glutamate receptors. In many neurological diseases, synapse structure and AMPA receptor function are altered, thus making AMPA receptors potential therapeutic targets for clinical intervention. The work summarized in this review suggests a link between AMPA receptor function and debilitating neuropathologies, and discusses the current state of therapies targeting AMPA receptors in four diseases. In amyotrophic lateral sclerosis, AMPA receptors allow cytotoxic levels of calcium into neurons, leading to motor neuron death. Likewise, in some epilepsies, overactivation of AMPA receptors leads to neuron damage. The same is true for ischemia, where oxygen deprivation leads to excitotoxicity. Conversely, Alzheimer's disease is characterized by decreased AMPA activation and synapse loss. Unfortunately, many clinical studies have had limited success by directly targeting AMPA receptors in these diseases. We also discuss how the use of AMPA receptor modulators, commonly known as ampakines, in neurological diseases initially seemed promising in animal studies, but mostly ineffective in clinical trials. We propose that indirectly affecting AMPA receptors, such as by modulating transmembrane AMPA receptor regulatory proteins or, more generally, by regulating glutamatergic transmission, may provide new therapeutic potential for neurological disorders.

Primary motor and premotor cortex in implicit sequence learning--evidence for competition between implicit and explicit human motor memory systems.

Abstract: Implicit and explicit memory systems for motor skills compete with each other during and after motor practice. Primary motor cortex (M1) is known to be engaged during implicit motor learning, while dorsal premotor cortex (PMd) is critical for explicit learning. To elucidate the neural substrates underlying the interaction between implicit and explicit memory systems, adults underwent a randomized crossover experiment of anodal transcranial direct current stimulation (AtDCS) applied over M1, PMd or sham stimulation during implicit motor sequence (serial reaction time task, SRTT) practice. We hypothesized that M1-AtDCS during practice will enhance online performance and offline learning of the implicit motor sequence. In contrast, we also hypothesized that PMd-AtDCS will attenuate performance and retention of the implicit motor sequence. Implicit sequence performance was assessed at baseline, at the end of acquisition (EoA), and 24 h after practice (retention test, RET). M1-AtDCS during practice significantly improved practice performance and supported offline stabilization compared with Sham tDCS. Performance change from EoA to RET revealed that PMd-AtDCS during practice attenuated offline stabilization compared with M1-AtDCS and sham stimulation. The results support the role of M1 in implementing online performance gains and offline stabilization for implicit motor sequence learning. In contrast, enhancing the activity within explicit motor memory network nodes such as the PMd during practice may be detrimental to offline stabilization of the learned implicit motor sequence. These results support the notion of competition between implicit and explicit motor memory systems and identify underlying neural substrates that are engaged in this competition.

Different stressors produce excitation or inhibition of mesolimbic dopamine neuron activity: response alteration by stress pre-exposure.

Abstract: Stressors can exert a wide variety of responses, ranging from adaptive responses to pathological changes; moreover, recent studies suggest that mild stressors can attenuate the response of a system to major stressful events. We have previously shown that 2-week exposure to cold, a comparatively mild inescapable stressor, induced a pronounced reduction in ventral tegmental area (VTA) dopamine (DA) neuron activity, whereas restraint stress increases DA neuron activity. However, it is not known if these stressors differentially impact the VTA in a region-specific manner, if they differentially impact behavioral responses, or whether the effects of such different stressors are additive or antagonistic with regard to their impact on DA neuron firing. To address these questions, single-unit extracellular recordings were performed in anesthetized control rats and rats exposed to chronic cold, and tested after delivery of a 2-h restraint session. Chronic cold stress strongly attenuated the number of DA neurons firing in the VTA, and this effect occurred primarily in the medial and central VTA regions that preferentially project to reward-related ventral striatal regions. Chronic cold exposure also prevented the pronounced increase in DA neuron population activity without affecting the behavioral sensitization to amphetamine produced by restraint stress. Taken together, these data show that a prolonged inescapable mild stressor can induce plastic changes that attenuate the DA system response to acute stress.

Differential effects of brain-derived neurotrophic factor and neurotrophin-3 on hindlimb function in paraplegic rats

Abstract: We compared the effect of viral administration of brain-derived neurotrophic factor (BDNF) or neurotrophin 3 (NT-3) on locomotor recovery in adult rats with complete thoracic (T10) spinal cord transection injuries, in order to determine the effect of chronic neurotrophin expression on spinal plasticity. At the time of injury, BDNF, NT-3 or green fluorescent protein (GFP) (control) was delivered to the lesion via adeno-associated virus (AAV) constructs. AAV–BDNF was significantly more effective than AAV–NT-3 in eliciting locomotion. In fact, AAV–BDNF-treated rats displayed plantar, weight-supported hindlimb stepping on a stationary platform, that is, without the assistance of a moving treadmill and without step training. Rats receiving AAV–NT-3 or AAV–GFP were incapable of hindlimb stepping during this task, despite provision of balance support. AAV–NT-3 treatment did promote the recovery of treadmill-assisted stepping, but this required continuous perineal stimulation. In addition, AAV–BDNF-treated rats were sensitized to noxious heat, whereas AAV–NT-3-treated and AAV–GFP-treated rats were not. Notably, AAV–BDNF-treated rats also developed hindlimb spasticity, detracting from its potential clinical applicability via the current viral delivery method. Intracellular recording from triceps surae motoneurons revealed that AAV–BDNF significantly reduced motoneuron rheobase, suggesting that AAV–BDNF promoted the recovery of over-ground stepping by enhancing neuronal excitability. Elevated nuclear c-Fos expression in interneurons located in the L2 intermediate zone after AAV–BDNF treatment indicated increased activation of interneurons in the vicinity of the locomotor central pattern generator. AAV–NT-3 treatment reduced motoneuron excitability, with little change in c-Fos expression. These results support the potential for BDNF delivery at the lesion site to reorganize locomotor circuits.

Cortical circuit dysfunction and cognitive deficits in schizophrenia--implications for preemptive interventions.

Abstract: Schizophrenia is a devastating disorder that is common, usually chronic, frequently associated with substantial co-morbidity for addictive and medical disorders and, as a consequence, very costly in both personal and economic terms. At present, no proven means for preventing or modifying the course of the illness exist. This review discusses evidence supporting the ideas that: (i) impairments in certain cognitive processes are the core feature of schizophrenia; (ii) these cognitive impairments reflect abnormalities in specific cortical circuits; and (iii) these circuitry abnormalities arise during childhood-adolescence. The implications of these findings for the development and implementation of safe, preemptive, disease-modifying interventions in individuals at high risk for a clinical diagnosis of schizophrenia are considered.

Orexin / hypocretin 1 receptor antagonist reduces heroin self-administration and cue-induced heroin seeking

Abstract: The orexin/hypocretin system is involved in several addiction-related behaviors. In the present experiments, we examined the involvement of orexin in heroin reinforcement and relapse by administering the orexin 1 receptor antagonist SB-334867 prior to heroin self-administration or prior to cue-induced or heroin-induced reinstatement of extinguished heroin seeking in male Sprague Dawley rats. SB-334867 (30 mg/kg, intraperitoneal) reduced heroin intake during self-administration under fixed ratio-1 and progressive ratio schedules. SB-334867 also attenuated reinstatement of heroin seeking elicited by cues, but not reinstatement elicited by a heroin prime. These results indicate that orexin antagonism reduces heroin self-administration, and they support a role for orexin in cue-triggered drug relapse.

Transplantation of human central nervous system stem cells – neuroprotection in retinal degeneration

Abstract: Stem cells derived from the human brain and grown as neurospheres (HuCNS-SC) have been shown to be effective in treating central neurodegenerative conditions in a variety of animal models. Human safety data in neurodegenerative disorders are currently being accrued. In the present study, we explored the efficacy of HuCNS-SC in a rodent model of retinal degeneration, the Royal College of Surgeons (RCS) rat, and extended our previous cell transplantation studies to include an in-depth examination of donor cell behavior and phenotype post-transplantation. As a first step, we have shown that HuCNS-SC protect host photoreceptors and preserve visual function after transplantation into the subretinal space of postnatal day 21 RCS rats. Moreover, cone photoreceptor density remained relatively constant over several months, consistent with the sustained visual acuity and luminance sensitivity functional outcomes. The novel findings of this study include the characterization and quantification of donor cell radial migration from the injection site and within the subretinal space as well as the demonstration that donor cells maintain an immature phenotype throughout the 7 months of the experiment and undergo very limited proliferation with no evidence of uncontrolled growth or tumor-like formation. Given the efficacy findings and lack of adverse events in the RCS rat in combination with the results from ongoing clinical investigations, HuCNS-SC appear to be a well-suited candidate for cell therapy in retinal degenerative conditions.

MicroRNA‐132 regulates recognition memory and synaptic plasticity in the perirhinal cortex

Abstract: Evidence suggests that the acquisition of recognition memory depends upon CREB-dependent long-lasting changes in synaptic plasticity in the perirhinal cortex.The CREB-responsive microRNA miR-132 has been shown to regulate synaptic transmission and we set out to investigate a role for this microRNA in recognition memory and its underlying plasticity mechanisms. To this end we mediated the specific overexpression of miR-132 selectively in the rat perirhinal cortex and demonstrated impairment in short-term recognition memory. This functional deficit was associated with a reduction in both long-term depression and long-term potentiation. These results confirm that microRNAs are key coordinators of the intracellular pathways that mediate experience-dependent changes in the brain. In addition, these results demonstrate a role for miR-132 in the neuronal mechanisms underlying the formation of short-term recognition memory.

Topography of descending projections from anterior insular and medial prefrontal regions to the lateral habenula of the epithalamus in the rat.

Abstract: The epithalamic lateral nucleus of the habenula (LHb) plays a key role in regulating firing of dopamine and serotonin neurons in the midbrain and is thereby involved in various cognitive and affective behaviors. It is not yet clear, however, from where the LHb receives cognitive and affective information relevant to its regulation of the midbrain monoaminergic systems. The prefrontal cortex would be among the ideal sources. Here, using anterograde and retrograde tracer injections in the rat brain, we characterized the topography of the corticohabenular projections. Following injections of cholera toxin subunit B into the LHb, retrogradely labeled neurons were produced in the anterior insular, cingulate, prelimbic and infralimbic cortices. Consistent with this retrograde tracing, injections of biotinylated dextran amine (BDA) into these cortical regions labeled robust terminals in the LHb. Our quantification of the BDA-impregnated varicosities revealed that projections from the anterior insula terminated mainly in the intersection regions of the lateral and ventral two-thirds of the LHb, while projections from the cingulate cortex terminated mainly in the lateral two-thirds of the LHb. By comparison, BDA-labeled terminals originating from the medial prefrontal regions were contained mainly in the medial plus ventral one-third of LHb. Based on these data, we hypothesize that LHb provides a link for conveying cognitive and affective information from prefrontal and insular regions to the midbrain monoaminergic centers.

Mechanisms controlling the guidance of thalamocortical axons through the embryonic forebrain

Abstract: Thalamocortical axons must cross a complex cellular terrain through the developing forebrain, and this terrain has to be understood for us to learn how thalamocortical axons reach their destinations. Selective fasciculation, guidepost cells and various diencephalic and telencephalic gradients have been implicated in thalamocortical guidance. As our understanding of the relevant forebrain patterns has increased, so has our knowledge of the guidance mechanisms. Our aim here is to review recent observations of cellular and molecular mechanisms related to: the growth of thalamofugal projections to the ventral telencephalon, thalamic axon avoidance of the hypothalamus and extension into the telencephalon to form the internal capsule, the crossing of the pallial-subpallial boundary, and the growth towards the cerebral cortex. We shall review current theories for the explanation of the maintenance and alteration of topographic order in the thalamocortical projections to the cortex. It is now increasingly clear that several mechanisms are involved at different stages of thalamocortical development, and each contributes substantially to the eventual outcome. Revealing the molecular and cellular mechanisms can help to link specific genes to details of actual developmental mechanisms.

Generalization of value in reinforcement learning by humans

Abstract: Research in decision-making has focused on the role of dopamine and its striatal targets in guiding choices via learned stimulus-reward or stimulus-response associations, behavior that is well described by reinforcement learning theories. However, basic reinforcement learning is relatively limited in scope and does not explain how learning about stimulus regularities or relations may guide decision-making. A candidate mechanism for this type of learning comes from the domain of memory, which has highlighted a role for the hippocampus in learning of stimulus-stimulus relations, typically dissociated from the role of the striatum in stimulus-response learning. Here, we used functional magnetic resonance imaging and computational model-based analyses to examine the joint contributions of these mechanisms to reinforcement learning. Humans performed a reinforcement learning task with added relational structure, modeled after tasks used to isolate hippocampal contributions to memory. On each trial participants chose one of four options, but the reward probabilities for pairs of options were correlated across trials. This (uninstructed) relationship between pairs of options potentially enabled an observer to learn about option values based on experience with the other options and to generalize across them. We observed blood oxygen level-dependent (BOLD) activity related to learning in the striatum and also in the hippocampus. By comparing a basic reinforcement learning model to one augmented to allow feedback to generalize between correlated options, we tested whether choice behavior and BOLD activity were influenced by the opportunity to generalize across correlated options. Although such generalization goes beyond standard computational accounts of reinforcement learning and striatal BOLD, both choices and striatal BOLD activity were better explained by the augmented model. Consistent with the hypothesized role for the hippocampus in this generalization, functional connectivity between the ventral striatum and hippocampus was modulated, across participants, by the ability of the augmented model to capture participants' choice. Our results thus point toward an interactive model in which striatal reinforcement learning systems may employ relational representations typically associated with the hippocampus.

Basal ganglia activity patterns in parkinsonism and computational modeling of their downstream effects

Abstract: The availability of suitable animal models and of the opportunity to record electrophysiologic data in movement disorder patients undergoing neurosurgical procedures has allowed researchers to investigate parkinsonism-related changes in neuronal firing patterns in the basal ganglia and associated areas of thalamus and cortex. These studies have shown that parkinsonism is associated with increased activity in the basal ganglia output nuclei, along with an increase in burst discharges, oscillatory firing, and synchronous firing patterns throughout the basal ganglia. Computational approaches have the potential to play an important role in the interpretation of these data. Such efforts can provide a formalized view of neuronal interactions in the network of connections between basal ganglia, thalamus and cortex, allow for the exploration of possible contributions of particular network components to parkinsonism, and potentially result in new conceptual frameworks and hypotheses that can be subjected to biological testing. It has proven very difficult, however, to integrate the wealth of the experimental findings into coherent models of the disease. In this review, we provide an overview of the abnormalities in neuronal activity that have been associated with parkinsonism. Subsequently, we discuss some particular efforts to model the pathophysiologic mechanisms that may link abnormal basal ganglia activity to the cardinal parkinsonian motor signs and may help explain the mechanisms underlying the therapeutic efficacy of deep brain stimulation for Parkinson’s disease. We emphasize the logical structure of these computational studies, making clear the assumptions from which they proceed and the consequences and predictions that follow from these assumptions.