Formation of an auditory sensory representation in posterior striatum emerges during a brief temporal window of associative learning in normal and hearing-impaired gerbils

Abstract

Introduction: The posterior tail of the striatum receives dense inputs from sensory regions of cortex and thalamus, as well as midbrain dopaminergic innervation, providing a neural substrate for associative sensory learning. Previously, we have demonstrated that developmental hearing loss is associated with aberrant physiological states in striatal medium spiny neurons (MSNs).

Methods: Here we directly investigated auditory associative learning impairments in the striatum of adult Mongolian gerbils that underwent transient developmental hearing loss or sham hearing loss during the critical period of auditory development. We used electrophysiology to reveal significant changes to neuronal population responses in vivo and intrinsic and synaptic properties to medium spiny neurons in vitro as animals learned an appetitive "Go/No-Go" auditory discrimination task. For in vivo experiments a 64-channel electrode was implanted in the auditory region of the posterior tail of the striatum and neuronal recordings were carried out as animals learned the task. For in vitro experiments, corticostriatal slice preparations were made from animals on each day of training.

Results: In naïve animals from both groups there was limited to no phase locking to either auditory stimulus in vivo, and long term depression resulted from theta burst stimulation in vitro. Furthermore, intrinsic and synaptic properties in normal hearing animals were unaffected; however, the hearing loss group continued to show lowered synaptic inhibition, synaptic hyperexcitation, and suppressed intrinsic excitability in the hearing loss group. Starting around day 3-4 in both groups, the emergence of striatal medium spiny neuron phase locking to the auditory conditioning stimuli was observed in vivo. This occurred contemporaneous to an increased probability of theta burst induced LTP during MSN whole cell recording in vitro, and acquisition of the task as the correct rejection response significantly increased in the behaving animals. During the acquisition phase MSNs in the normal hearing group showed a significant decrease in synaptic inhibition and increase in synaptic excitation with no change to intrinsic excitability, while the MSNs in the hearing loss group showed a significant increase in synaptic inhibition, reduction of synaptic hyper excitability, and compensatory changes to intrinsic excitability that supported normal action potential generation. In both groups, synaptic properties were resolved to similar level of E/I balance that could be part of a conserved learning state.

Discussion: These changes to the intrinsic and synaptic properties likely support LTP induction in vivo and the strengthening of synapses between auditory inputs and MSNs that facilitate neuronal phase locking. These findings have significant implications for our understanding of striatal resilience to sensory impairments in early life, in addition to establishing a granular understanding of the striatal circuit changes that support reward driven stimulus-response learning.

Keywords: associative learning; auditory striatum; awake behaving recording; in vitro whole cell recording; in vivo electrophysiology; posterior striatum; tail striatum.

Figure 1

Phases of learning for the Amplitude Modulated Go No-Go Behavioral Task. (A) Photomicrographs showing an AAV tracer injection (AAV1.CamkII.GFP) into primary auditory cortex and subsequent labeling in the posterior tail of the striatum. (B) Cartoon showing the placement of the 64-channel electrode, and the relative positions of the recording sites recovered after histology. (C) Scatter plot showing the selection criterion for putative medium spiny neurons after PCA sorting, with an exemplar MSN waveform. (D) Auditory brainstem response data showing the sound attenuation produced by earplugging (top) and a diagram of the critical period hearing loss (bottom). (E) Diagram showing the behavioral paradigm. After nose poke a Go or NoGo auditory stimulus will play directing the animal to go to the trough or initiate a new trial with a re-poke. (F) Diagram showing how d-prime is calculated and how the behavioral epochs are determined by d-prime cutoffs. (G) Behavioral curves for the group average and individual animal data for normal hearing and hearing loss animals with and without electrode implants. (H,I) Bar plots showing the average and individual animal behavioral latency for Go and NoGo trials in normal hearing and hearing loss groups. ^*p < 0.05, ^**p < 0.01, and ^***p < 0.001. FA, false alarm; CR, correct rejection; NH, normal hearing; HL, hearing loss; Acq, acquisition.

Figure 2

Neuronal stimulus response profiles during Go and NoGo Trials on the amplitude modulated discrimination task. (A) Diagram showing the behavioral response possibilities during a Go trial (top, left) and the average hit and miss percentages for implanted NH and HL animals over 10 days of training (bottom, left). (Right) Stimulus response profiles for Go trials during the three phases of learning for the normal hearing and hearing loss groups. (B) Cartoon showing the possible outcomes of the NoGo Trial (top, left) and the group average incidence rates of FA and CR for NH and HL animals over 10 days of training (bottom, left). (Right) Stimulus response profiles for NoGo trials during the three phases of learning for the normal hearing and hearing loss groups. (C) Plots showing the shifts in peak latency to firing for the 4 Hz Go stimulus (left) and the 12 Hz NoGo stimulus (right) throughout learning for the NH and HL groups. (D) Cumulative frequency distributions of the neural population data for latency to peak firing in Naïve versus mastery phases of learning for NH and HL groups during Go (left) and NoGo (right) trials. FA, false alarm; CR, correct rejection; NH, normal hearing; HL, hearing loss; Acq, acquisition.

Figure 3

Heat maps for NH and HL animals during Go and NoGo trials for each behavioral epoch. (A) Heat map showing the changes to sound induced neural activity during go (left) and No-Go (right) trials in normal hearing animals as they progress from naive to mastery of the task. In each heat map the 2 days of data used in analysis for each animal for each epoch are displayed. (B) Scatter plots showing the latency to peak firing rates for all animals in the NH group during Go (left) and NoGo (right) trials across behavioral epochs. (C) Heat map showing the changes to sound induced neural activity during go (left) and No-Go (right) trials in hearing loss animals as they progress from naive to mastery of the task. In each heat map the 2 days of data used in analysis for each animal for each epoch are displayed. (D) Scatter plots showing the latency to peak firing rates for all animals in the HL group during Go (left) and NoGo (right) trials across behavioral epochs.

Figure 4

Changes in neural population response to nose poke and unmodulated sound during task acquisition. (A) Cartoon showing that the Go and NoGo trial are approximately the same prior to modulated sound onset. As such the neural response to the nosepoke and non-modulated sound onset is the same across Go and NoGo trials (right). Neural suppression and increased latency to peak firing occur during task acquisition for both trial types (bottom). (B) Stimulus response profiles for Go (color) and NoGo (grey) trials during the three phases of learning for the NH and HL groups. (C) Bar plots showing the group average and individual animal data for changes in latency to peak (top) and peak firing rates (bottom) across learning for the Go and NoGo trials in the NH group. (D) Bar plots showing the group average and individual animal data for changes in latency to peak (top) and peak firing rates (bottom) across learning for the Go and NoGo trials in the HL group. ^*p < 0.05, ^**p < 0.01, and ^***p < 0.001. FA, false alarm; CR, correct rejection; NH, normal hearing; HL, hearing loss; Acq, acquisition.

Figure 5

Changes in neural population response to reward and punishment during task acquisition. (A) Cartoon showing the changes in neural activity to the reward in the Go trial are suppressed during task acquisition for both groups. (B) Stimulus response profiles for Go trials during the three phases of learning for the NH and HL groups. (C) Cartoon showing the changes in neural activity to the punishment (timeout) in the No-Go FA trial are suppressed during task acquisition for both groups. (D) Stimulus response profiles for NoGo trials during the three phases of learning for the NH and HL groups. (E) Scattergrams showing the mean average and individual population data for peak firing rate to the reward during the Go Hit trial for both the NH and HL groups. (F) Scattergrams showing the mean average and individual population data for peak firing rate to the punishment during the No-Go FA trial for both the NH and HL groups. ^*p < 0.05, ^**p < 0.01, and ^***p < 0.001. FA, false alarm; CR, correct rejection; NH, normal hearing; HL, hearing loss; Acq, acquisition.

Figure 6

A brief window of synaptic and intrinsic plasticity during task acquisition. (A) Diagram showing the corticostriatal slice preparation. (B) Left shows representative examples of a medium spiny neuron evoked response to 300 pa and −30 pA. Middle, shows line plots of the F/I curves for the NH and HL group over behavioral phases. Right, top shows bar plots of the NH and HL group averages for rheobase over behavioral phases. Right, bottom shows bar plots of the NH and HL group averages for resistance over behavioral phases. (C) Shows a diagram of the slice configuration for recording IPSPs in vitro (left) Middle shows line plots of the IPSP slopes for the NH and HL group over behavioral phases. Right, top shows bar plots of the NH and HL group averages for min evoked IPSP amplitudes over behavioral phases. Right, bottom shows bar plots of the NH and HL group averages for max evoked IPSP amplitudes over behavioral phases. (D) Shows a diagram of the slice configuration for recording EPSPs in vitro (left). Middle shows line plots of the EPSP slopes for the NH and HL group over behavioral phases. Right, top shows bar plots of the NH and HL group averages for min evoked IPSP amplitudes over behavioral phases. Right, bottom shows bar plots of the NH and HL group averages for action potential (AP) thresholds over behavioral phases. (E) Shows a diagram for the configuration for theta burst induced LTP in the slice preparation (left). Middle shows bar plots for the mean average potentiation data for NH and HL animals over behavioral phases (top) and the individual animal data for LTP and LTD expression (bottom). (F) Behavioral data showing d-prime data for NH and HL animals over 10 days of training that received daily cannula infusions of NMDA blocker (AP-5, 50 mM, 2 mL). ^*p < 0.05, ^**p < 0.01, and ^***p < 0.001. LTP, long term potentiation; LTD, long term depression; Vm, resting voltage; TBS, theta burst stimulation; IPSP, inhibitory post synaptic potential; EPSP, excitatory post synaptic potential; NH, normal hearing; HL, hearing loss; pA, pico amps; mV, millivolts; M, medial; R, rostral; aud str, auditory striatum; aud ctx, auditory cortex; ACSF, artificial cerebrospinal fluid.

Figure 7

A brief window of plasticity supports the emergence of neural population responses to conditioned auditory stimuli. (A) Diagram showing the baseline differences between NH and HL animals E/I tone, firing rates, and how these shift to a conserved meta plastic state during task acquisition. (B) Diagram illustrating causal versus acausal action potential generation across the corticostriatal circuit. (C) Diagram showing spike timing dependent plasticity driven by causal action potential generation across the corticostriatal circuit. (D) Diagram showing the temporal parameters behind spike timing dependent plasticity. (E) A diagram showing how the changes to E/I tone and firing rate support LTP induction during a brief window of plasticity for the NH and HL group. (F) A diagram showing the emergence of the neural response to the 4 Hz Go and 12 Hz No-Go stimulus in the striatum in the context of the default presence of the stimulus response in auditory cortex.