Dysfunctional behavioral modulation of corticostriatal communication in the R6/2 mouse model of Huntington's disease (original) (raw)
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Cortical circuit alterations precede motor impairments in Huntington’s disease mice
Scientific Reports
Huntington's disease (HD) is a devastating hereditary movement disorder, characterized by degeneration of neurons in the striatum and cortex. studies in human patients and mouse HD models suggest that disturbances of neuronal function in the neocortex play an important role in disease onset and progression. However, the precise nature and time course of cortical alterations in HD have remained elusive. Here, we use chronic in vivo two-photon calcium imaging to longitudinally monitor the activity of identified single neurons in layer 2/3 of the primary motor cortex in awake, behaving R6/2 transgenic HD mice and wildtype littermates. R6/2 mice show age-dependent changes in cortical network function, with an increase in activity that affects a large fraction of cells and occurs rather abruptly within one week, preceeding the onset of motor defects. Furthermore, quantitative proteomics demonstrate a pronounced downregulation of synaptic proteins in the cortex, and histological analyses in R6/2 mice and human HD autopsy cases reveal a reduction in perisomatic inhibitory synaptic contacts on layer 2/3 pyramidal cells. Taken together, our study provides a timeresolved description of cortical network dysfunction in behaving HD mice and points to disturbed excitation/inhibition balance as an important pathomechanism in HD.
Neurobiology of …, 2010
Altered neuronal activity in the striatum appears to be a key component of Huntington’s disease (HD), a fatal, neurodegenerative condition. To assess this hypothesis in freely behaving transgenic rats that model HD (tgHDs), we used chronically implanted micro-wires to record the spontaneous activity of striatal neurons. We found that relative to wild-type controls, HD rats suffer from population-level deficits in striatal activity characterized by a loss of correlated firing and fewer episodes of coincident spike bursting between simultaneously recorded neuronal pairs. These results are in line with our previous report of marked alterations in the pattern of striatal firing in mouse models of HD that vary in background strain, genetic construct, and symptom severity. Thus, loss of coordinated spike activity in striatum appears to be a common feature of HD pathophysiology, regardless of HD model variability.
Alterations in cortical excitation and inhibition in genetic mouse models of Huntington's disease
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2009
Previously, we identified progressive alterations in spontaneous excitatory (EPSCs) and inhibitory (IPSCs) postsynaptic currents in the striatum of the R6/2 mouse model of Huntington's disease (HD). Medium-sized spiny neurons (MSNs) from these mice displayed a lower frequency of EPSCs and a population of cells exhibited an increased frequency of IPSCs beginning at about 40 days, a time point when the overt behavioral phenotype begins. The cortex provides the major excitatory drive to the striatum and is affected during disease progression. We examined spontaneous EPSCs and IPSCs of somatosensory cortical pyramidal neurons in layers II/III in slices from three different mouse models of HD, the R6/2, the YAC128 and the CAG140 knock-in. Results revealed that spontaneous EPSCs occurred at a higher frequency and evoked EPSCs were larger in behaviorally phenotypic mice while spontaneous IPSCs were initially increased in frequency in all models and subsequently decreased in R6/2 mice after they displayed the typical R6/2 overt behavioral phenotype. Changes in miniature IPSCs and evoked IPSC paired-pulse ratios suggested altered probability of GABA release. Also, in R6/2 mice, blockade of GABA A receptors induced complex discharges in slices and seizures in vivo at all ages. In conclusion, altered excitatory and inhibitory inputs to pyramidal neurons in the cortex in HD appear to be a prevailing deficit throughout the development of the disease. Furthermore, the differences between synaptic phenotypes in cortex and striatum are important for the development of future therapeutic approaches, which may need to be targeted early in the development of the phenotype.
Disrupted temporal control in the R6/2 mouse model of Huntington’s disease
Behavioral Neuroscience, 2009
Huntington's disease is characterized by corticostriatal dysfunction and degeneration of the striatum with progressive loss of the medium spiny neurons. These circuits are important for instrumental responding, interval timing, and temporal control over motor output. We investigated the acquisition of timed operant responding in two R6/2 Huntington's Disease models, differing in CAG repeat length and genetic background (115 and 250 CAG repeats, and a mixed CBAxC57 or pure C57 background) and their corresponding wild type controls using the peak procedure. Both mouse lines exhibited similar response control deficits. In unreinforced peak trials, mice either did not learn to terminate an ongoing response past reinforcement time or required more trials to acquisition compared to the wild type mice. While transgenic and wild type mice did not exhibit differences in temporal accuracy, response curves were flatter in transgenic mice, suggesting decreased temporal control over operant responding. The results are discussed in terms of the neurobiology of interval timing, instrumental responding, and the neuropathology of HD and R6/2 mice.
Cognitive functions and corticostriatal circuits: insights from Huntington's disease
Trends in Cognitive Sciences, 1998
Interest in the information-processing capabilities of anatomically-defined segregated corticostriatal circuits (see ) has spawned a number of conceptual and computational models from workers in a variety of disparate disciplines, ranging from robotics to neuropsychology 1-3 . Insights into the functions of the basal ganglia in human subjects can be achieved through the study of behavioural and cognitive symptoms resulting from neurodegenerative diseases such as Parkinson's disease (PD) and Huntington's disease (HD), which afflict these structures. The striking movement abnormalities caused by PD and HD have supported the view of the basal ganglia as structures important in movement control. However, it is evident that both of these disorders encompass more than simply motor deficits, with impairments in the cognitive and psychiatric domains increasingly becoming major foci of research. PD and HD affect basal ganglia function in very different ways; PD mainly through the degeneration of nigro-striatal dopaminergic circuitry, beginning in the putamen, and HD through the degeneration of the striatum itself, probably beginning in the caudate nucleus. These separate forms of pathology and their associations with distinctive motor symptoms, akinesia in PD and chorea in HD, suggest the possibility of qualitative differences in otherwise overlapping cognitive deficits, that might provide additional clues about the functioning of distinct parts of the striatal circuitry.
Altered Information Processing in the Prefrontal Cortex of Huntington's Disease Mouse Models
Journal of Neuroscience, 2008
Understanding cortical information processing in Huntington's disease (HD), a genetic neurological disorder characterized by prominent motor and cognitive abnormalities, is key to understanding the mechanisms underlying the HD behavioral phenotype. We recorded extracellular spike activity in two symptomatic, freely behaving mouse models: R6/2 transgenics, which are based on a CBA ϫ C57BL/6 background and show robust behavioral symptoms, and HD knock-in (KI) mice, which have a 129sv background and express relatively mild behavioral signs. We focused on prefrontal cortex and assessed firing patterns of individually recorded neurons as well as the amount of synchrony between simultaneously recorded neuronal pairs. At the single-unit level, spike trains in R6/2 transgenics were less variable and had a faster rate than their corresponding wild-type (WT) littermates but showed significantly less bursting. In contrast, KI and WT firing patterns were closely matched. An assessment of both WTs revealed that the R6/2 and KI difference could not be explained by a difference in WT electrophysiology. Thus, the altered pattern of individual spike trains in R6/2 mice appears to parallel their aggressive form of symptom expression. Both WT lines, however, showed a high proportion of synchrony between neuronal pairs (Ͼ85%) that was significantly attenuated in both corresponding HD models (decreases of ϳ20% and ϳ30% in R6/2s and knock-ins, respectively). The loss of spike synchrony, regardless of symptom severity, suggests a population-level deficit in cortical information processing that underlies HD progression.
Journal of Huntington's Disease, 2016
Aberrant communication between striatum, the main information processing unit of the basal ganglia, and cerebral cortex plays a critical role in the emergence of Huntington's disease (HD), a fatal monogenetic condition that typically strikes in the prime of life. Although both striatum and cortex undergo substantial cell loss over the course of HD, corticostriatal circuits become dysfunctional long before neurons die. Understanding the dysfunction is key to developing effective strategies for treating a progressively worsening triad of motor, cognitive, and psychiatric symptoms. Cortical output neurons drive striatal activity through the release of glutamate, an excitatory amino acid. Striatal outputs, in turn, release ␥-amino butyric acid (GABA) and exert inhibitory control over downstream basal ganglia targets. Ample evidence from transgenic rodent models points to dysregulation of corticostriatal glutamate transmission along with corresponding changes in striatal GABA release as underlying factors in the HD behavioral phenotype. Another contributor is dysregulation of dopamine (DA), a modulator of both glutamate and GABA transmission. In fact, pharmacological manipulation of DA is the only currently available treatment for HD symptoms. Here, we review data from animal models and human patients to evaluate the role of DA in HD, including DA interactions with glutamate and GABA within the context of dysfunctional corticostriatal circuitry.
Impaired cortico-striatal functional connectivity in prodromal Huntington's Disease
Neuroscience letters, 2012
Huntington's Disease (HD) is a neurodegenerative disease caused by a CAG triplet-repeat expansion-mutation in the Huntingtin gene. Subjects at risk for HD can be identified by genetic testing in the prodromal phase. Structural changes of basal-ganglia nuclei such as the caudate nucleus are well-replicated findings observable early in prodromal-HD subjects and may be preceded by distinct functional alterations of cortico-striatal circuits. This study aims to assess functional integrity of the motor system as a cortico-striatal circuit with particular clinical relevance in HD. Ten subjects in the prodromal phase of HD and ten matched controls were administered blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) at rest (3T). Functional connectivity was measured as synchrony of BOLD activity between the caudate nucleus and thirteen cortical brain regions (seeds). Basal-ganglia volumes were assessed as established markers of disease progression in prodr...
Disrupted striatal neuron inputs and outputs in Huntington's disease
CNS Neuroscience & Therapeutics, 2018
The most prominent neuropathology in HD occurs in the striatal part of the basal ganglia, in which progressive loss of projection neurons leads to severe striatal atrophy. 1 Although striatal projection neuron (SPN) loss is associated with the prominent motor symptoms as HD progresses, more subtle functional deficits are evident already in premanifest stages of HD. Premanifest HD individuals are impaired, for example, in the initiation and/or execution of motor tasks. 2-13 As striatal neuron loss is minimal in premanifest HD, 1,14,15 early symptoms are likely to be largely driven by striatal neuron circuit level connectivity loss and dysfunction. Consistent with this, the early motor symptoms in premanifest HD develop in parallel with gradual loss of cerebral and striatal white matter, 16-23 increasing striatal hypometabolism, 17,24 and reduced striatal activation during behavioral tasks, 25,26 all indicative of decreased cortical input to striatal neurons. Among the major sources of input to the striatum, shrinkage and eventually marked neuronal loss are seen in deep layers of the cerebral cortex that project to striatum and in cerebral white matter. 27-30 Thalamus as well is a source of major input to striatum, and it shows substantial neuronal loss by late in disease. 27,29,30 Thus, in addition to the well-documented