Dysfunctional Behavioral Modulation of Corticostriatal Communication in the R6/2 Mouse Model of Huntington’s Disease

Background In Huntington’s disease (HD), motor symptoms develop prior to the widespread loss of neurons in striatum and cerebral cortex. The aim of this study was to examine dysfunctional patterns of corticostriatal communication during spontaneously occurring behaviors in a transgenic mouse model of HD. Methodology/Principal Findings Local field potentials (LFPs) were recorded from two closely interconnected areas, motor cortex and dorsal striatum, in wild-type controls (WT, n = 14) and a widely used transgenic HD model (R6/2 mice, n = 12). All mice were between the ages of 7–9 weeks, a critical period of motor symptom development in R6/2s. Recordings were obtained while the mice were behaving freely in an open field. Specific LFP activity was extracted using timestamps for three increasingly demanding motor behaviors: 1) resting; 2) grooming; and 3) active exploration. Power spectral densities (PSD) were obtained for the cortical and striatal LFPs as well as coherence levels and relative phase across the frequency spectrum. In both brain regions, only R6/2s showed high frequency LFP oscillations during rest and grooming. As behavior increased from resting to exploring, corticostriatal synchrony at high frequencies declined in R6/2s, completely opposite to the WT pattern. R6/2s also exhibited nearly in-phase corticostriatal activity (cortex phase leads of ∼5°), while the WTs consistently showed cortical phase lags of ∼20° across all assessed behaviors, indicating a lead role for striatum. Conclusions/Significance Our results add to growing evidence for altered communication between cortex and striatum in HD and suggest more generally that increasingly demanding motor behaviors differentially modulate corticostriatal communication. Our data also suggest conduction delays in R6/2 corticostriatal transmission, leading to compensatory speeding of LFP activity, as evidenced by the presence of high frequency LFP oscillations.

[1]  H. Eichenbaum,et al.  Oscillatory Entrainment of Striatal Neurons in Freely Moving Rats , 2004, Neuron.

[2]  B. Harper.  Huntington Disease , 2005, Journal of the Royal Society of Medicine.

[3]  A. Graybiel,et al.  Differential Dynamics of Activity Changes in Dorsolateral and Dorsomedial Striatal Loops during Learning , 2010, Neuron.

[4]  G. Rebec,et al.  Corticostriatal dysfunction and glutamate transporter 1 (GLT1) in Huntington's disease: interactions between neurons and astrocytes. , 2012, Basal ganglia.

[5]  F. Saudou,et al.  Huntington's disease knock-in male mice show specific anxiety-like behaviour and altered neuronal maturation , 2012, Neuroscience Letters.

[6]  Stephen B. Dunnett,et al.  Characterization of Progressive Motor Deficits in Mice Transgenic for the Human Huntington’s Disease Mutation , 1999, The Journal of Neuroscience.

[7]  G. Rebec,et al.  Altered Neural and Behavioral Dynamics in Huntington's Disease: An Entropy Conservation Approach , 2012, PloS one.

[8]  Louis G. Castonguay,et al.  Worry, generalized anxiety disorder, and emotion: Evidence from the EEG gamma band , 2008, Biological Psychology.

[9]  A. Pérez-Villalba.  Rhythms of the Brain, G. Buzsáki. Oxford University Press, Madison Avenue, New York (2006), Price: GB £42.00, p. 448, ISBN: 0-19-530106-4 , 2008 .

[10]  Adam Ponzi,et al.  Sequentially Switching Cell Assemblies in Random Inhibitory Networks of Spiking Neurons in the Striatum , 2010, The Journal of Neuroscience.

[11]  Samuel P. Burns,et al.  Comparisons of the Dynamics of Local Field Potential and Multiunit Activity Signals in Macaque Visual Cortex , 2010, The Journal of Neuroscience.

[12]  A. Engel,et al.  Different Subtypes of Striatal Neurons Are Selectively Modulated by Cortical Oscillations , 2009, The Journal of Neuroscience.

[13]  P. Fries.  A mechanism for cognitive dynamics: neuronal communication through neuronal coherence , 2005, Trends in Cognitive Sciences.

[14]  James J. Pekar,et al.  Impaired cortico-striatal functional connectivity in prodromal Huntington's Disease , 2012, Neuroscience Letters.

[15]  Daniel K. Leventhal,et al.  Basal Ganglia Beta Oscillations Accompany Cue Utilization , 2012, Neuron.

[16]  Carlos Cepeda,et al.  The corticostriatal pathway in Huntington's disease , 2007, Progress in Neurobiology.

[17]  Michael Okun,et al.  The Subthreshold Relation between Cortical Local Field Potential and Neuronal Firing Unveiled by Intracellular Recordings in Awake Rats , 2010, The Journal of Neuroscience.

[18]  M. MacDonald,et al.  Systematic behavioral evaluation of Huntington's disease transgenic and knock-in mouse models , 2009, Neurobiology of Disease.

[19]  J. Donoghue,et al.  Neural discharge and local field potential oscillations in primate motor cortex during voluntary movements. , 1998, Journal of neurophysiology.

[20]  X. Leinekugel,et al.  “Ectopic” theta oscillations and interictal activity during slow-wave state in the R6/1 mouse model of Huntington's disease , 2012, Neurobiology of Disease.

[21]  Ann M Graybiel,et al.  Oscillations of local field potentials in the rat dorsal striatum during spontaneous and instructed behaviors. , 2007, Journal of neurophysiology.

[22]  Scott J Barton,et al.  Altered Information Processing in the Prefrontal Cortex of Huntington's Disease Mouse Models , 2008, The Journal of Neuroscience.

[23]  Scott J Barton,et al.  Dysregulated information processing by medium spiny neurons in striatum of freely behaving mouse models of Huntington's disease. , 2008, Journal of neurophysiology.

[24]  Bijan Pesaran,et al.  Uncovering the Mysterious Origins of Local Field Potentials , 2009, Neuron.

[25]  Rui M. Costa,et al.  Rapid Alterations in Corticostriatal Ensemble Coordination during Acute Dopamine-Dependent Motor Dysfunction , 2006, Neuron.

[26]  George Paxinos,et al.  The Mouse Brain in Stereotaxic Coordinates , 2001 .