Changes in striatal procedural memory coding correlate with learning deficits in a mouse model of Huntington disease

Abstract

In hereditary neurodegenerative Huntington disease (HD), early cognitive impairments before motor deficits have been hypothesized to result from dysfunction in the striatum and cortex before degeneration. To test this hypothesis, we examined the firing properties of single cells and local field activity in the striatum and cortex of pre-motor-symptomatic R6/1 transgenic mice while they were engaged in a procedural learning task, the performance on which typically depends on the integrity of striatum and basal ganglia. Here, we report that a dramatically diminished recruitment of the vulnerable striatal projection cells, but not local interneurons, of R6/1 mice in coding for the task, compared with WT littermates, is associated with severe deficits in procedural learning. In addition, both the striatum and cortex in these mice showed a unique oscillation at high γ-frequency. These data provide crucial information on the in vivo cellular processes in the corticostriatal pathway through which the HD mutation exerts its effects on cognitive abilities in early HD.

Fig. 1.

Diminished recruitment of putative MSNs recorded in R6/1 mice during behavioral task. (A) Typical waveform of MSN and putative fast spiking INs. Spike peak-to-valley width (d) was used to classify cell types. (B) Frequency histograms of spike widths (d in A) for all cells recorded in WT and R6/1 mice. (C) Mean (±SEM) numbers of INs and MSNs recorded per probe (tetrode) throughout recording sessions in two groups. (****Significant difference between the two genotypes at P < 0.0001.) (D) Schematic representation of tetrode placements in the striatum for all mice of both genotypes (WT, left; R6/1, right). Tetrode positions from different anteroposterior axis were stacked onto a unique coronal plan at 0.7 mm anterior to Bregma. (E and F) Photographs of a mouse carrying electrode implant and head stage during recording and the operant chamber used during recording.

Fig. 2.

High γ-oscillation in the striatum in R6/1. (A) Proportions of cells oscillating at low (<10 Hz, slow) and high (50-80 Hz, fast) frequencies in both genotypes. (B) Relative frequency distribution of γ-oscillations frequencies for all fast oscillatory cells in R6/1 mice. (C) Proportions of pairs of neurons with slow (<10 Hz) and fast (50–80 Hz) oscillations in both genotypes. (D) Relative frequency distribution of oscillatory frequencies among fast oscillatory pairs of cells in R6/1 mice. (E and F) Power spectra of session-wide striatal LFP by FFT averaged for each genotype and training stage (early, E; late, F). (G) Typical example of a coherent IN at a frequency around 70 Hz. Coherence value is display by the black line (left axis) and the phase by the red line (right axis). (H) Percentage of unit-to-LFP coherent INs and MSNs in both genotypes. (I and J) Coherence frequency distribution and phase relationship with high γ-cycle for coherent cells in R6/1 mice.

Fig. 3.

Task-related firings of striatal neurons and procedural learning ability. Examples of task-responsive activity of an MSN for WT (A) and R6/1 (B) mice around three periods delimited by NP, L, and EX events: period I (between NP and L, green) contains animal's approach to reward following NP action, period II (between L and EX, orange) corresponds to reward consumption, and period III (between EX and NP, blue) is characterized by the initiation of a new trial and NP. Period I is represented to illustrate repeated and circular nature of the events. Thick red bars symbolize periods during which firing rates increased significantly. (C) Proportion of striatal cells (both types combined) presenting inhibition or activation during the three behavioral periods in both groups. (D) Typical acquisition curves for two WT and R6/1 mice. (E) Examples of performance progression within and between sessions over three consecutive days in a representative WT and R6/1 mice. On day n, both mice at midstage of learning performed similarly (70 responses, seventh session for WT, and 77 responses, 32nd session for R6/1 mice), but R6/1 mouse showed slower improvement between sessions than WT mouse did. Graph displays the mean response rate/min averaged every 5 min. (F) The mean cumulative hours required for WT and R6/1 mice to learn the NP–reward association (***P < 0.001). (G) Asymptotic performance levels reached by both genotypes (*P < 0.01). (H) Average running speed throughout trainings. (I) Changes in the proportions of task-responsive MSN and IN across three or four performance levels in both groups of mice. Because R6/1 mice rarely reached more than 200 responses per session, only three levels were analyzed for them. (J) The proportions of MSNs and INs showing the task responsiveness throughout the three (in R6/1 mice) or four (in WT mice) different stages of training shown in I.

Fig. 4.

PETHs revealing high γ- and β-oscillations in R6/1 mice. (A–D) PETHs around (±2.75 s) the L (A and B) and EX (C and D) for representative WT (A and C) and R6/1 mice (B and D). White lines in A–D represent the average moving speed of the animal. Red arrows represent γ-band, and black arrows and dotted lines represent β-band. (E) Spatial positions of a R6/1 mouse in the operant chamber when his striatal LFP expressed high γ-oscillation (blue dots, green dots show visited pixels). Red circle indicates the location of food well. (F) Spectrogram for 8 s showing the variation of the power densities for low (<30 Hz) and high (70–80 Hz) frequency bands. Dark horizontal bars indicate periods when the mouse consumed reward.

Fig. 5.

Cortical high γ-oscillation in R6/1 mice. (A and B) Power spectra of session-wide cortical LFP by FFT averaged for each genotype and training stage. (C) Percentage of cells coherent to cortical LFP in both genotypes. (D and E) Coherence frequency distribution and phase relationship with high γ-cycle for coherent cortical cells in R6/1 mice.