Reinstatement of synaptic plasticity in the aging brain through specific dopamine transporter inhibition.

Aging-related neurological deficits negatively impact mental health, productivity, and social interactions leading to a pronounced socioeconomic burden. Since declining brain dopamine signaling during aging is associated with the onset of neurological impairments, we produced a selective dopamine transporter (DAT) inhibitor to restore endogenous dopamine levels and improve cognitive function. We describe the synthesis and pharmacological profile of (S,S)-CE-158, a highly specific DAT inhibitor, which increases dopamine levels in brain regions associated with cognition. We find both a potentiation of neurotransmission and coincident restoration of dendritic spines in the dorsal hippocampus, indicative of reinstatement of dopamine-induced synaptic plasticity in aging rodents. Treatment with (S,S)-CE-158 significantly improved behavioral flexibility in scopolamine-compromised animals and increased the number of spontaneously active prefrontal cortical neurons, both in young and aging rodents. In addition, (S,S)-CE-158 restored learning and memory recall in aging rats comparable to their young performance in a hippocampus-dependent hole board test. In sum, we present a well-tolerated, highly selective DAT inhibitor that normalizes the age-related decline in cognitive function at a synaptic level through increased dopamine signaling.

Differential effects of the mode of touch, active and passive, on experience-driven plasticity in the S1 cutaneous digit representation of adult macaque monkeys.

This study compared the receptive field (RF) properties and firing rates of neurons in the cutaneous hand representation of primary somatosensory cortex (areas 3b, 1, and 2) of 9 awake, adult macaques that were intensively trained in a texture discrimination task using active touch (fingertips scanned over the surfaces using a single voluntary movement), passive touch (surfaces displaced under the immobile fingertips), or both active and passive touch. Two control monkeys received passive exposure to the same textures in the context of a visual discrimination task. Training and recording extended over 1-2 yr per animal. All neurons had a cutaneous receptive field (RF) that included the tips of the stimulated digits (D3 and/or D4). In area 3b, RFs were largest in monkeys trained with active touch, smallest in those trained with passive touch, and intermediate in those trained with both; i.e., the mode of touch differentially modified the cortical representation of the stimulated fingers. The same trends were seen in areas 1 and 2, but the changes were not significant, possibly because a second experience-driven influence was seen in areas 1 and 2, but not in area 3b: smaller RFs with passive exposure to irrelevant tactile inputs compared with recordings from one naive hemisphere. We suggest that added feedback during active touch and higher cortical firing rates were responsible for the larger RFs with behavioral training; this influence was tempered by periods of more restricted sensory feedback during passive touch training in the active + passive monkeys.NEW & NOTEWORTHY We studied experience-dependent sensory cortical plasticity in relation to tactile discrimination of texture using active and/or passive touch. We showed that neuronal receptive fields in primary somatosensory cortex, especially area 3b, are largest in monkeys trained with active touch, smallest in those trained with passive touch, and intermediate in those trained using both modes of touch. Prolonged, irrelevant tactile input had the opposite influence in areas 1 and 2, favoring smaller receptive fields.

Attentional deficits and altered neuronal activation in medial prefrontal and posterior parietal cortices in mice with reduced dopamine transporter levels.

The executive control function of attention is regulated by the dopaminergic (DA) system. Dopamine transporter (DAT) likely plays a role in controlling the influence of DA on cognitive processes. We examined the effects of DAT depletion on cognitive processes related to attention. Mice with the DAT gene genetically deleted (DAT+/- heterozygotes) were compared to wild type (WT) mice on the Attentional Set-Shifting Task (ASST). Changes in neuronal activity during the ASST were shown with early growth response genes 1 and 2 (egr-1 and egr-2) immunohistochemistry in the medial prefrontal cortex (mPFC) and in the posterior parietal cortex (PPC). Heterozygotes were impaired in tasks that tax reversal learning, attentional-set formation and set-shifting. Densities of egr-2 labeled cells in the mPFC were lower in mutant mice when compared with wild-types in intradimensional shift of attention (IDS), extradimensional shift of attention and extradimensional shift of attention-reversal phases of the ASST task, and in PPC in the IDS phase of the task. The results demonstrate impairments of the areas associated with attentional functions in DAT+/- mice and show that an imbalance of the dopaminergic system has an impact on the complex attention-related executive functions.

Low-Affinity/High-Selectivity Dopamine Transport Inhibition Sufficient to Rescue Cognitive Functions in the Aging Rat.

The worldwide increase in cognitive decline, both in aging and with psychiatric disorders, warrants a search for pharmacological treatment. Although dopaminergic treatment approaches represent a major step forward, current dopamine transporter (DAT) inhibitors are not sufficiently specific as they also target other transporters and receptors, thus showing unwanted side effects. Herein, we describe an enantiomerically pure, highly specific DAT inhibitor, S-CE-123, synthetized in our laboratory. Following binding studies to DAT, NET and SERT, GPCR and kinome screening, pharmacokinetics and a basic neurotoxic screen, S-CE-123 was tested for its potential to enhance and/or rescue cognitive functions in young and in aged rats in the non-invasive reward-motivated paradigm of a hole-board test for spatial learning. In addition, an open field study with young rats was carried out. We demonstrated that S-CE-123 is a low-affinity but highly selective dopamine reuptake inhibitor with good bioavailability. S-CE-123 did not induce hyperlocomotion or anxiogenic or stereotypic behaviour in young rats. Our compound improved the performance of aged but not young rats in a reward-motivated task. The well-described impairment of the dopaminergic system in aging may underlie the age-specific effect. We propose S-CE-123 as a possible candidate for developing a tentative therapeutic strategy for age-related cognitive decline and cognitive dysfunction in psychiatric disorders.

Rapid, learning-induced inhibitory synaptogenesis in murine barrel field.

The structure of neurons changes during development and in response to injury or alteration in sensory experience. Changes occur in the number, shape, and dimensions of dendritic spines together with their synapses. However, precise data on these changes in response to learning are sparse. Here, we show using quantitative transmission electron microscopy that a simple form of learning involving mystacial vibrissae results in approximately 70% increase in the density of inhibitory synapses on spines of neurons located in layer IV barrels that represent the stimulated vibrissae. The spines contain one asymmetrical (excitatory) and one symmetrical (inhibitory) synapse (double-synapse spines), and their density increases threefold as a result of learning with no apparent change in the density of asymmetrical synapses. This effect seems to be specific for learning because pseudoconditioning (in which the conditioned and unconditioned stimuli are delivered at random) does not lead to the enhancement of symmetrical synapses but instead results in an upregulation of asymmetrical synapses on spines. Symmetrical synapses of cells located in barrels receiving the conditioned stimulus also show a greater concentration of GABA in their presynaptic terminals. These results indicate that the immediate effect of classical conditioning in the "conditioned" barrels is rapid, pronounced, and inhibitory.

A critical speed for gating of tactile detection during voluntary movement.

This study addressed the paradoxical observation that movement is essential for tactile exploration, and yet is accompanied by movement-related gating or suppression of tactile detection. Knowing that tactile gating covaries with the speed of movement (faster movements, more gating), we hypothesized that there would be no tactile gating at slower speeds of movement, corresponding to speeds commonly used during tactile exploration (<200 mm/s). Subjects (n = 21) detected the presence or absence of a weak electrical stimulus applied to the skin of the right middle finger during two conditions: rest and active elbow extension. Movement speed was systematically varied from 50 to ~1,000 mm/s. No subject showed evidence of tactile gating at the slowest speed tested, 50 mm/s (rest versus movement), but all subjects showed decreased detection at one or more higher speeds. For each subject, we calculated the critical speed, corresponding to the speed at which detection fell to 0.5 (chance). The mean critical speed was 472 mm/s and >200 mm/s in almost all subjects (19/21). This result is consistent with our hypothesis that subjects optimize the speed of movement during tactile exploration to avoid speeds associated with tactile gating. This strategy thus maximizes the quality of the tactile feedback generated during tactile search and improves perception.

The Association between Executive Functions and Body Weight/BMI in Children and Adolescents with ADHD.

Despite the increasing body of research on Attention Deficit Hyperactivity Disorder (ADHD), the results of the studies assessing the relationship between executive function deficit and the risk of obesity in people with ADHD are incongruent. Our study aimed to assess the relationship between measures of executive functions and body weight and Body Mass Index (BMI) in children and adolescents with ADHD and control subjects. The study group consisted of 58 subjects aged from 8 to 17 years with ADHD. The Control group consisted of 62 healthy age and sex-matched participants from primary and secondary schools. Weight, height, and BMI measurements were standardized. The Sustained Attention to Response Test (SART) and the Attention Network Test (ANT) were used to assess executive functions. Based on the analysis of the correlation and analysis of moderation, we found that subjects with higher weight in the study group presented a lower efficiency of the inhibition processes and gave more impulsive and incorrect answers. The occurrence of impulsive reactions might contribute to the risk of excessive weight in children and adolescents with ADHD.

Resting state dynamic functional connectivity in children with attention deficit/hyperactivity disorder.

Attention deficit/hyperactivity disorder (ADHD) is characterized by inattention, hyperactivity and impulsivity. In this study, we investigated group differences in dynamic functional connectivity (dFC) between 113 children with inattentive (46 ADHDI) and combined (67 ADHDC) ADHD and 76 typically developing (TD) children using resting-state functional MRI data. For dynamic connectivity analysis, the data were first decomposed into 100 independent components, among which 88 were classified into eight well-known resting-state networks (RSNs). Three discrete FC states were then identified using k-means clustering and used to estimate transition probabilities between states in both patient and control groups using a hidden Markov model. Our results showed state-dependent alterations in intra and inter-network connectivity in both ADHD subtypes in comparison with TD. Spending less time than healthy controls in state 1, both ADHDIand ADHDCwere characterized with weaker intra-hemispheric connectivity with functional asymmetries. In this state, ADHDIfurther showed weaker inter-hemispheric connectivity. The patients spent more time in state 2, exhibiting characteristic abnormalities in corticosubcortical and corticocerebellar connectivity. In state 3, a less frequently state observed across the ADHD and TD children, ADHDCwas differentiated from ADHDIby significant alterations in FC between bilateral temporal regions and other brain areas in comparison with TD. Across all three states, several strategic brain regions, mostly bilateral, exhibited significant alterations in both static functional connectivity (sFC) and dFC in the ADHD groups compared to TD, including inferior, middle and superior temporal gyri, middle frontal gyri, insula, anterior cingulum cortex, precuneus, calcarine, fusiform, superior motor area, and cerebellum. Our results show distributed abnormalities in sFC and dFC between different large-scale RSNs including cortical and subcortical regions in both ADHD subtypes compared to TD. Our findings show that the dynamic changes in brain FC can better explain the underlying pathophysiology of ADHD such as deficits in visual cognition, attention, memory and emotion processing, and cognitive and motor control.

Disrupted Functional Rich-Club Organization of the Brain Networks in Children with Attention-Deficit/Hyperactivity Disorder, a Resting-State EEG Study.

Growing evidence indicates that disruptions in the brain's functional connectivity play an important role in the pathophysiology of ADHD. The present study investigates alterations in resting-state EEG source connectivity and rich-club organization in children with inattentive (ADHDI) and combined (ADHDC) ADHD compared with typically developing children (TD) under the eyes-closed condition. EEG source analysis was performed by eLORETA in different frequency bands. The lagged phase synchronization (LPS) and graph theoretical metrics were then used to examine group differences in the topological properties and rich-club organization of functional networks. Compared with the TD children, the ADHDI children were characterized by a widespread significant decrease in delta and beta LPS, as well as increased theta and alpha LPS in the left frontal and right occipital regions. The ADHDC children displayed significant increases in LPS in the central, temporal and posterior areas. Both ADHD groups showed small-worldness properties with significant increases and decreases in the network degree in the θ and ß bands, respectively. Both subtypes also displayed reduced levels of network segregation. Group differences in rich-club distribution were found in the central and posterior areas. Our findings suggest that resting-state EEG source connectivity analysis can better characterize alterations in the rich-club organization of functional brain networks in ADHD patients.

The SLC6A3 gene polymorphism is related to the development of attentional functions but not to ADHD.

Neuropharmacological and human clinical studies have suggested that the brain dopaminergic system is substantively involved in normal and pathological phenotypes of attention. Dopamine transporter gene (SLC6A3) was proposed as a candidate gene for Attention-Deficit/Hyperactivity Disorder (ADHD). We investigated the effect of the SLC6A3 variants on cognitive performance in ADHD and healthy children and teenagers. Participants completed cognitive tasks measuring attentional switching, selective and sustained attention, and effectiveness of alerting, orienting and executive attention. We estimated the effects of 40 bp variable number of tandem repeat (VNTR) polymorphism located in the 3' untranslated region (3' UTR) (9-repeat vs 10-repeat allele) of the SLC6A3 gene, ADHD diagnosis, age, and their interactions as predictors of cognitive performance. ADHD children demonstrated deficits in most of the examined attention processes, persistent within the examined age range (9-16 years). No significant effects were observed for the interaction of ADHD and the SLC6A3 polymorphism, but the results revealed a significant main effect of SLC6A3 genotype in the entire research sample. Subjects carrying 9R allele performed the switching task significantly worse in comparison to children with 10R/10R or 10R/11R genotype. SLC6A3 polymorphism moderated age-related improvements in orienting and attentional switching. Results suggest that SLC6A3 genotype influence these attentional/cognitive functions which deficits are not the key symptoms in ADHD.

Cortical source analysis of resting state EEG data in children with attention deficit hyperactivity disorder.

OBJECTIVE: This study investigated age-dependent and subtype-related alterations in electroencephalography (EEG) power spectra and current source densities (CSD) in children with attention deficit and hyperactivity disorder (ADHD). METHODS: We performed spectral and cortical source (exact low-resolution electromagnetic tomography, eLORETA) analyses using resting state EEG recordings from 40 children (8-16 years) with combined and inattentive subtypes of ADHD and 41 age-matched healthy controls (HC). Group differences in EEG spectra and CSD were investigated at each scalp location, voxel and cortical region in delta, theta, alpha and beta bands. We also explored associations between topographic changes in EEG power and CSD and age. RESULTS: Compared to healthy controls, combined ADHD subtype was characterized with significantly increased diffuse theta/beta power ratios (TBR) with a widespread decrease in beta CSD. Inattentive ADHD subtype presented increased TBR in all brain regions except in posterior areas with a global increase in theta source power. In both ADHD and HC, older age groups showed significantly lower delta source power and TBR and higher alpha and beta source power than younger age groups. Compared to HC, ADHD was characterized with increases in theta fronto-central and temporal source power with increasing age. CONCLUSIONS: Our results confirm that TBR can be used as a neurophysiological biomarker to differentiate ADHD from healthy children at both the source and sensor levels. SIGNIFICANCE: Our findings emphasize the importance of performing the source imaging analysis in order to better characterize age-related changes in resting-state EEG activity in ADHD and controls.

Potential role of dopamine transporter in behavioral flexibility.

Behavioral flexibility is subserved by the prefrontal cortex and the basal ganglia. Orbitofrontal cortex (OFC) and dorsomedial striatum (DMS) form a functional frontocorticostriatal circuit crucial for the mediation of flexibility during reversal learning via dopamine (DA) neurotransmission. The regulatory control in maintaining DA homeostasis and function is provided by the dopamine transporter (DAT), which therefore likely plays a significant role in controlling the influence of DA on cognitive processes. Here we used a gene knockout mouse model to investigate the role of DAT in the performance on the Attentional Set-Shifting Task (ASST) stages dependent upon the OFC and the DMS. Additionally, behavior of mice after repeated administration of selective DAT inhibitor, GBR 12909, was examined. The animals were treated with the inhibitor to elicit a compensatory DAT up-regulation following withdrawal. Learning was slower and the number of errors during reversal learning and intra-dimensional shift stages was higher in DAT+/- mutant mice than in WT mice. GBR 12909-treated mice had deficits in reversal stages of the ASST. Neuronal activation in the OFC and DMS during the ASST was examined with early growth response proteins 1 and 2 (egr-1, egr-2) immunohistochemistry. Density of egr-2 labeled cells in the OFC was lower in mutant mice than in wild-types during reversal learning and the expression of the egr-1 was lower in mutant mice in the OFC and DMS during reversal and intra-dimensional shift stages. Mice with decreased DAT levels displayed behavioral difficulties that were accompanied by a lower task-induced activation of neurons in brain regions involved in the reversal learning. Altogether, these data indicate the role of the DAT in the behavioral flexibility.

Age-Related Changes in Resting-State EEG Activity in Attention Deficit/Hyperactivity Disorder: A Cross-Sectional Study.

Numerous studies indicate that attention deficit/hyperactivity disorder (ADHD) is related to some developmental trends, as its symptoms change widely over time. Nevertheless, the etiology of this phenomenon remains ambiguous. There is a disagreement whether ADHD is related to deviations in brain development or to a delay in brain maturation. The model of deviated brain development suggests that the ADHD brain matures in a fundamentally different way, and does not reach normal maturity at any developmental stage. On the contrary, the delayed brain maturation model assumes that the ADHD brain indeed matures in a different, delayed way in comparison to healthy age-matched controls, yet eventually reaches proper maturation. We investigated age-related changes in resting-state EEG activity to find evidence to support one of the alternative models. A total of 141 children and teenagers participated in the study; 67 diagnosed with ADHD and 74 healthy controls. The absolute power of delta, theta, alpha, and beta frequency bands was analyzed. We observed a significant developmental pattern of decreasing absolute EEG power in both groups. Nonetheless, ADHD was characterized by consistently lower absolute EGG power, mostly in the theta frequency band, in comparison to healthy controls. Our results are in line with the deviant brain maturation theory of ADHD, as the observed effects of age-related changes in EEG power are parallel but different in the two groups.

Deficits in experience-dependent cortical plasticity and sensory-discrimination learning in presymptomatic Huntington's disease mice.

Huntington's disease (HD) is one of a group of neurodegenerative diseases caused by an expanded trinucleotide (CAG) repeat coding for an extended polyglutamine tract. The disease is inherited in an autosomal dominant manner, with onset of motor, cognitive, and psychiatric symptoms typically occurring in midlife, followed by unremitting progression and eventual death. We report here that motor presymptomatic R6/1 HD mice show a severe impairment of somatosensory-discrimination learning ability in a behavioral task that depends heavily on the barrel cortex. In parallel, there are deficits in barrel-cortex plasticity after a somatosensory whisker-deprivation paradigm. The present study demonstrates deficits in neocortical plasticity correlated with a specific learning impairment involving the same neocortical area, a finding that provides new insight into the cellular basis of early cognitive deficits in HD.

Behavioral verification of associative learning in whiskers-related fear conditioning in mice.

Fear-conditioning is one of the most widely used paradigms in attempts to unravel the processes and mechanisms underlying learning and plasticity. In most of the Pavlovian conditioning paradigms auditory stimulus is used as a conditioned stimulus (CS), but conditioning can be accomplished also to tactile CS. The whisker-to-barrel tactile system in mice offers convenient way to investigate the brain pathways and mechanisms of learning, and plasticity of the brain cortex. To support a claim that an animal learns during conditioning session and that the plastic changes are associative in nature, objective measures of behavior are necessary. Multiple types of conditioned responses can develop, depending on the training situation, CS and unconditioned stimulus (UCS) characteristics. These include physiological responses, such as salivation, heart rate, galvanic skin reaction, and also behavioral responses, such as startle reflex potentiation or suppression of the ongoing behavior. When studying learning with the whisker system in behaving mice, stimulation of individual whiskers in a well-controlled manner may require animal restrain with a disadvantage of only limited behavioral responses observed. Stimulation of whiskers in the neck-restraining apparatus evokes head movements. When whiskers stimulation (CS) is paired with an aversive UCS during conditioning, the head movements decrease in the course of the training. This reaction, called minifreezing, resembles freezing response, frequently used behavioral measure, however applicable only in freely moving animals. This article will review experimental evidences confirming that minifreezing is a relevant index of association formation between the neutral CS and the and the aversive UCS.

Involvement of retrosplenial cortex in classical conditioning.

The cingulate cortex, which comprises of two major subdivisions - anterior cingulate cortex (CG) and retrosplenial cortex (RSP), is implicated in many cognitive functions. The RSP is an important node in the systemic integration network. Studies point to its role in learning that involves spatial stimuli and navigation. Relatively little is known about its involvement in simple learning such as classical conditioning. We examined the involvement of the two cytoarchitectonic divisions, agranular and granular, of the rostral and caudal RSP in a delay conditioning, where stimulation of the facial vibrissae was paired with a tail shock. During the conditioning session the [(14)C]-2-deoxyglucose (2DG) brain mapping was performed. Effectiveness of conditioning was assessed with frequency of head movements, which decreased in the course of the conditioning. 2DG uptake in RSP and additionally in CG was examined in conditioned, pseudoconditioned and stimulated control groups. The metabolic labeling was elevated in caudal and rostral both RSP and CG in the conditioned group, but not in animals which received CS or UCS alone. Comparison between conditioned and pseudoconditioned groups showed the specific activation by associative learning in both divisions of the rostral RSP and rostral CG. Counts of c-Fos expressing nuclei confirmed activation of the rostral RSP in the CS+UCS group. These data support the concept of RSP as structure that, besides its recognized role in visuospatial learning, monitors and reacts to activity of brain systems responsible for other types of learning and, together with CG, subserve cognitive processes, with simple associative learning among them.

Brain activation patterns during classical conditioning with appetitive or aversive UCS.

The neural bases of appetitive and aversive conditioning are different, and at various stages of learning, may engage distinct cortical and subcortical networks. Using [14C]2-deoxyglucose (2-DG) autoradiography, we examined brain activation in mice during the first and the third sessions of a classical conditioning involving stimulation of whiskers on one side of the muzzle (conditioned stimulus, CS) paired with an aversive or appetitive unconditioned stimulus (UCS). The nucleus basalis magnocellularis showed stronger labelling during appetitive conditioning while the lateral hypothalamus was activated only during aversive pairing session. Also, in the appetitive training (both conditioning and pseudoconditioning), the ventral pallidum responded differently than in the aversive situation. A tendency for higher labelling of basolateral amygdala was noted in aversive conditioning. Somatosensory thalamic nuclei, as well as posterior parietal cortex and nucleus accumbens core, were strongly activated in both conditions during the first training session, but only by appetitive conditioning during the third session. With the exception of the nucleus basalis, ventral pallidum and lateral hypothalamus, appetitive or aversive classical conditioning increased 2-DG uptake in a similar set of brain structures. Activation of nucleus accumbens core, posterior parietal cortex, and structures of the somatosensory pathway decreases with the duration of training presumably due to different involvement of attention and different dynamics of the two variants of conditioning.

Early-phase of learning enhances communication between brain hemispheres.

In the somatosensory system, inputs from one side of the body are only transmitted to the contralateral primary somatosensory cortex, but both sides of the body representation can interact via interhemispheric connections. These interactions depend on the behavioural requirements of the animal and its level of arousal. During the process of learning, alertness and attention may modify the responsiveness of neuronal pathways. We functionally mapped the brains of mice by using [14C]2-deoxyglucose (2DG) autoradiography during the first and the third session of a classical conditioning paradigm, involving whiskers stimulation on one side of the muzzle paired with an aversive or appetitive unconditioned stimulus. During the first pairing session, an increased 2DG uptake was seen in the barrel cortex of both hemispheres, independently of the type of applied unconditioned stimulus. In the third session of the sensory pairing, activation of the barrel cortex was solely contralateral, as expected after unilateral whisker stimulation. Thus, sensory stimulation directed to one cerebral hemisphere during the initial stages of Pavlovian conditioning activates the primary sensory area in both hemispheres. These results suggest that during the early phase of conditioning, when alertness is presumably strongest, the interhemispheric interactions are enhanced.

Reduced plasticity of cortical whisker representation in adult tenascin-C-deficient mice after vibrissectomy.

The effect of the extracellular matrix recognition molecule tenascin-C on cerebral plasticity induced by vibrissectomy was investigated with 2-deoxyglucose (2DG) brain mapping in tenascin-C-deficient mice. Unilateral vibrissectomy sparing row C of vibrissae was performed in young adult mice. Two months later, cortical representations of spared row C vibrissae and control row C on the other side of the snout were visualized by [(14)C]2DG autoradiography. In both wild-type and tenascin-C-deficient mice, cortical representation of the spared row was expanded in all layers of the barrel cortex. However, the effect was significantly more extensive in wild-type animals than in the mutant. Elimination of tenascin-C by genetic manipulation thus reduces the effect of vibrissectomy observed in the somatosensory cortex. No increase in number of fibres in the vibrissal nerve of spared vibrissae was seen, and occurrence of additional nerve to the spared follicle was very rare. Thus, in tenascin-C-deficient mice functional plasticity seems to be impaired within the CNS.

Impaired learning-dependent cortical plasticity in Huntington's disease transgenic mice.

Huntington's disease (HD) is a genetically transmitted neurodegenerative disorder. The neuropathology in HD is a selective neuronal cell death in several brain regions including cortex. Although changes in synaptic plasticity were shown within the hippocampus and striatum of HD transgenic mice, there are no studies considering neocortical synaptic plasticity abnormalities in HD. We examined the impact of the HD transgene upon learning-dependent plasticity of cortical representational maps. The effect of associative learning, in which stimulation of a row of vibrissae was paired with appetitive stimulus, upon functional representations of vibrissae in the barrel cortex, was investigated with 2-deoxyglucose brain mapping in presymptomatic R6/1 HD mice. In wild-type mice, cortical representation of the row of vibrissae involved in the training was expanded, while in HD mice the representation of this row was not expanded. The results suggest that presymptomatic R6/1 HD transgenic mice show deficits in plasticity of primary somatosensory cortex.