Limits...
Dysregulated Neuronal Activity Patterns Implicate Corticostriatal Circuit Dysfunction in Multiple Rodent Models of Huntington's Disease.

Miller BR, Walker AG, Barton SJ, Rebec GV - Front Syst Neurosci (2011)

Bottom Line: Among simultaneously recorded neuron pairs, correlated firing was reduced in all brain regions of all models, while coincident bursting, which measures the temporal overlap between bursting pairs, was reduced in striatum of all models as well as in M1 of R6/2s.Collectively, our results indicate that disrupted corticostriatal processing occurs across multiple HD models despite differences in the severity of the behavioral phenotype.Efforts aimed at normalizing corticostriatal activity may hold the key to developing new HD therapeutics.

View Article: PubMed Central - PubMed

Affiliation: Program in Neuroscience and Department of Psychological and Brain Sciences, Indiana University Bloomington, IN, USA.

ABSTRACT
Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder that targets the corticostriatal system and results in progressive deterioration of cognitive, emotional, and motor skills. Although cortical and striatal neurons are widely studied in animal models of HD, there is little information on neuronal function during expression of the HD behavioral phenotype. To address this knowledge gap, we used chronically implanted micro-wire bundles to record extracellular spikes and local field potentials (LFPs) in truncated (R6/1 and R6/2) and full-length (knock-in, KI) mouse models as well as in transgenic HD rats (tgHD rats) behaving in an open-field arena. Spike activity was recorded in the striatum of all models and in prefrontal cortex (PFC) of R6/2 and KI mice, and in primary motor cortex (M1) of R6/2 mice. We also recorded LFP activity in R6/2 striatum. All HD models exhibited altered neuronal activity relative to wild-type (WT) controls. Although there was no consistent effect on firing rate across models and brain areas, burst firing was reduced in striatum, PFC, and M1 of R6/2 mice, and in striatum of KI mice. Consistent with a decline in bursting, the inter-spike-interval coefficient of variation was reduced in all regions of all models, except PFC of KI mice and striatum of tgHD rats. Among simultaneously recorded neuron pairs, correlated firing was reduced in all brain regions of all models, while coincident bursting, which measures the temporal overlap between bursting pairs, was reduced in striatum of all models as well as in M1 of R6/2s. Preliminary analysis of striatal LFPs revealed aberrant behavior-related oscillations in the delta to theta range and in gamma activity. Collectively, our results indicate that disrupted corticostriatal processing occurs across multiple HD models despite differences in the severity of the behavioral phenotype. Efforts aimed at normalizing corticostriatal activity may hold the key to developing new HD therapeutics.

No MeSH data available.


Related in: MedlinePlus

Representative cross-correlograms constructed from a pair of WT and R6/2 striatal neurons (left column) and a pair of WT and R6/2 M1 cortical neurons (right column). The two horizontal lines in each plot indicate the 95% confidence intervals. The two WT peaks exceed the upper confidence interval, indicating significance. Note the different time scales between striatum and cortical cross-correlograms indicating either correlated or synchronous firing, respectively. Striatal and M1 neuron pairs show markedly reduced coherent spike activity (flat and non-significant peak). We note that we have yet to find repetitive peaks and troughs in the cross-correlograms, which indicates oscillatory firing activity between neuronal pairs.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3100808&req=5

Figure 2: Representative cross-correlograms constructed from a pair of WT and R6/2 striatal neurons (left column) and a pair of WT and R6/2 M1 cortical neurons (right column). The two horizontal lines in each plot indicate the 95% confidence intervals. The two WT peaks exceed the upper confidence interval, indicating significance. Note the different time scales between striatum and cortical cross-correlograms indicating either correlated or synchronous firing, respectively. Striatal and M1 neuron pairs show markedly reduced coherent spike activity (flat and non-significant peak). We note that we have yet to find repetitive peaks and troughs in the cross-correlograms, which indicates oscillatory firing activity between neuronal pairs.

Mentions: We also assessed the temporal relationship in spiking between simultaneously recorded pairs of neurons. For this analysis, we constructed cross-correlograms, and in each case, peaks in the histogram that exceeded the confidence interval were defined as significantly coherent neuronal pairs. Interestingly, as shown in Figure 2, the temporal dynamics between coherent spiking differs between cortical and striatal neurons. For example, cortical neuron pairs tend to spike in precise temporal or “synchronized” coherence (Sakurai and Takahashi, 2006; Walker et al., 2008), whereas striatal neuron pairs discharge with much broader temporal coherence (Miller et al., 2008b; Ponzi and Wickens, 2010). In all cases, however, we found a marked reduction in temporally coherent neuronal activity from all brain areas and all HD models recorded.


Dysregulated Neuronal Activity Patterns Implicate Corticostriatal Circuit Dysfunction in Multiple Rodent Models of Huntington's Disease.

Miller BR, Walker AG, Barton SJ, Rebec GV - Front Syst Neurosci (2011)

Representative cross-correlograms constructed from a pair of WT and R6/2 striatal neurons (left column) and a pair of WT and R6/2 M1 cortical neurons (right column). The two horizontal lines in each plot indicate the 95% confidence intervals. The two WT peaks exceed the upper confidence interval, indicating significance. Note the different time scales between striatum and cortical cross-correlograms indicating either correlated or synchronous firing, respectively. Striatal and M1 neuron pairs show markedly reduced coherent spike activity (flat and non-significant peak). We note that we have yet to find repetitive peaks and troughs in the cross-correlograms, which indicates oscillatory firing activity between neuronal pairs.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3100808&req=5

Figure 2: Representative cross-correlograms constructed from a pair of WT and R6/2 striatal neurons (left column) and a pair of WT and R6/2 M1 cortical neurons (right column). The two horizontal lines in each plot indicate the 95% confidence intervals. The two WT peaks exceed the upper confidence interval, indicating significance. Note the different time scales between striatum and cortical cross-correlograms indicating either correlated or synchronous firing, respectively. Striatal and M1 neuron pairs show markedly reduced coherent spike activity (flat and non-significant peak). We note that we have yet to find repetitive peaks and troughs in the cross-correlograms, which indicates oscillatory firing activity between neuronal pairs.
Mentions: We also assessed the temporal relationship in spiking between simultaneously recorded pairs of neurons. For this analysis, we constructed cross-correlograms, and in each case, peaks in the histogram that exceeded the confidence interval were defined as significantly coherent neuronal pairs. Interestingly, as shown in Figure 2, the temporal dynamics between coherent spiking differs between cortical and striatal neurons. For example, cortical neuron pairs tend to spike in precise temporal or “synchronized” coherence (Sakurai and Takahashi, 2006; Walker et al., 2008), whereas striatal neuron pairs discharge with much broader temporal coherence (Miller et al., 2008b; Ponzi and Wickens, 2010). In all cases, however, we found a marked reduction in temporally coherent neuronal activity from all brain areas and all HD models recorded.

Bottom Line: Among simultaneously recorded neuron pairs, correlated firing was reduced in all brain regions of all models, while coincident bursting, which measures the temporal overlap between bursting pairs, was reduced in striatum of all models as well as in M1 of R6/2s.Collectively, our results indicate that disrupted corticostriatal processing occurs across multiple HD models despite differences in the severity of the behavioral phenotype.Efforts aimed at normalizing corticostriatal activity may hold the key to developing new HD therapeutics.

View Article: PubMed Central - PubMed

Affiliation: Program in Neuroscience and Department of Psychological and Brain Sciences, Indiana University Bloomington, IN, USA.

ABSTRACT
Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder that targets the corticostriatal system and results in progressive deterioration of cognitive, emotional, and motor skills. Although cortical and striatal neurons are widely studied in animal models of HD, there is little information on neuronal function during expression of the HD behavioral phenotype. To address this knowledge gap, we used chronically implanted micro-wire bundles to record extracellular spikes and local field potentials (LFPs) in truncated (R6/1 and R6/2) and full-length (knock-in, KI) mouse models as well as in transgenic HD rats (tgHD rats) behaving in an open-field arena. Spike activity was recorded in the striatum of all models and in prefrontal cortex (PFC) of R6/2 and KI mice, and in primary motor cortex (M1) of R6/2 mice. We also recorded LFP activity in R6/2 striatum. All HD models exhibited altered neuronal activity relative to wild-type (WT) controls. Although there was no consistent effect on firing rate across models and brain areas, burst firing was reduced in striatum, PFC, and M1 of R6/2 mice, and in striatum of KI mice. Consistent with a decline in bursting, the inter-spike-interval coefficient of variation was reduced in all regions of all models, except PFC of KI mice and striatum of tgHD rats. Among simultaneously recorded neuron pairs, correlated firing was reduced in all brain regions of all models, while coincident bursting, which measures the temporal overlap between bursting pairs, was reduced in striatum of all models as well as in M1 of R6/2s. Preliminary analysis of striatal LFPs revealed aberrant behavior-related oscillations in the delta to theta range and in gamma activity. Collectively, our results indicate that disrupted corticostriatal processing occurs across multiple HD models despite differences in the severity of the behavioral phenotype. Efforts aimed at normalizing corticostriatal activity may hold the key to developing new HD therapeutics.

No MeSH data available.


Related in: MedlinePlus