Stimulation of Midbrain Dopaminergic Structures Modifies Firing Rates of Rat Lateral Habenula Neurons

Ventral tegmental area (VTA) and substantia nigra pars compacta (SNpc) are midbrain structures known to be involved in mediating reward in rodents. Lateral habenula (LHb) is considered as a negative reward source and it is reported that stimulation of the LHb rapidly induces inhibition of firing in midbrain dopamine neurons. Interestingly, the phasic fall in LHb neuronal activity may follow the excitation of dopamine neurons in response to reward-predicting stimuli. The VTA and SNpc give rise to dopaminergic projections that innervate the LHb, which is also known to be involved in processing painful stimuli. But it's unclear what physiological effects these inputs have on habenular function. In this study we distinguished the LHb pain-activated neurons of the Wistar rats and assessed their electrophysiological responsiveness to the stimulation of the VTA and SNpc with either single-pulse stimulation (300 µA, 0.5 Hz) or tetanic stimulation (80 µA, 25 Hz). Single-pulse stimulation that was delivered to either midbrain structure triggered transient inhibition of firing of ∼90% of the LHb pain-activated neurons. However, tetanic stimulation of the VTA tended to evoke an elevation in neuronal firing rate. We conclude that LHb pain-activated neurons can receive diverse reward-related signals originating from midbrain dopaminergic structures, and thus participate in the regulation of the brain reward system via both positive and negative feedback mechanisms

Comparisons between responses of LHb PA neurons to the single-pulse stimuli of respective dopaminergic structures.

<p>(a) The latency to onset of the cessation induced by the SNpc stimulus is notably longer than that induced by the VTA stimulus. (b) The duration of cessation in firing of PA neurons in response to the SNpc stimuli seems much more marked than the one in response to the VTA stimuli. Black asterisks indicate a significant difference (<i>P</i><0.05). (c, d) Average activity of LHb PA neurons during single-pulse stimulation of the VTA (filled rhombus, n = 17) and the SNpc (open rhombus, n = 20), respectively. Single (<i>P</i><0.005) and double black asterisks (<i>P</i><0.0001) indicate a marked firing suppression compared with baseline (0 ms to 100 ms). Error bars indicate SEM.</p

Electrolytic lesions of the fasciculus retroflexus.

<p>(a) Intact bilateral fasciculus retroflexus are shown in this panel. (b) Electrolytic lesions caused complete lesions (n = 9; average area proportion >90%). (c) Partial lesions were found in some animals (n = 6; average area proportion >60%). fr, fasciculus retroflexus; ml, medial leminscicus; D3V, dorsal third ventricle; 3V, third ventricle.</p

Effects of the fasciculus retroflexus lesions on LHb PA neuron firing.

<p>(a, b left panels) The bilateral lesions attenuated the rapid inhibitory effect of the single-pulse VTA and SNpc stimulation on the LHb PA neurons. Peristimulus time histograms were compiled from 100 consecutive sweeps and each single stimulus pulse was delivered at 100 ms (bin: 1 ms). (a, b right panels) Firing rates of these pain-activated neurons recorded in the VTA and SNpc stimuli groups were suppressed after the lesions (bin: 5 s).</p

Effects of single-pulse stimulations of the VTA and the SNpc on the LHb PA neurons.

<p>The recordings of panels a, b and c are from different neurons. (a, b, c left panels) The LHb PA neurons generally exhibited a similar transient cessation in firing in response to the single-pulse VTA stimulation and the single-pulse SNpc stimulation. The left panel c showed an original firing recording for the LHb PA neuron's response to single-pulse stimulations of the VTA. Both the peristimulus time histograms were comprised of 100 consecutive sweeps. Each single stimulus pulse was delivered 100 ms after the onset of each sweep (bin: 1 ms; a, b left panels). (a, b, c right panels) PA neuron firing was increased by the tetanic VTA stimulus and the tetanic SNpc stimulus. The right panel c showed an original firing recording for the LHb PA neuron's response to the tetanic VTA stimulus. Both histograms displayed using a bin of 5 s (a, b right panels). (d) an original firing recording for the LHb PA neuron's response to tail pinch.</p

Region-specific characteristic of activated LHb PA neurons to tetanic VTA stimuli.

<p>Due to limited number of the PA neurons which showed suppression in firing, these numbers are added to those present no response to the VTA stimulus during performing the <i>χ</i>² test.</p

Distribution of recorded LHb PA neurons.

<p>Distribution of recorded LHb PA neurons.</p