Diencephalic and Mesencephalic Substrate for Brain Stimulation Reward

Electrical stimulation of certain brain regions in laboratory animals induces a rewarding effect that is strong enough to support operant responding; for instance, rats will learn to press a lever to receive a short train of electrical pulses in these regions. This behavior, termed intracranial-self stimulation (ICSS), has been extensively employed to characterize the neural substrate underlying reward and goal-directed behaviors. Evidence over the past few years suggests that the dorsal diencephalic conduction system (DDC) and the tail of the ventral tegmental area (tVTA) are involved in the rewarding effect of ICSS (or brain stimulation reward). However, despite significant progress in research, the underlying mechanisms remain largely unknown. The overarching goal of this thesis is to investigate the role of the DDC and the tVTA in brain stimulation reward. Three research articles are presented in this thesis. The first article evaluates the effect of serial electrolytic lesions at the DDC and the medial forebrain bundle (MFB)— another pathway involved in brain stimulation reward—on the reward signal triggered by ICSS of the lateral hypothalamus (LH) and the dorsal raphe (DR) in rats. Results show that lesions at both the DDC and MFB produce larger and longer-lasting attenuations in brain stimulation reward than individual lesions at either pathway alone, and are more effective in attenuating the reward signal induced by LH self-stimulation. In the second article of the thesis, stimulation-induced Fos-like immunoreactivity (FLIR), a marker of cellular activity, was combined with electrolytic lesions at the DDC to determine whether the same nuclei that are active in lesion-naïve rats continue to be active following the lesions. Results show that electrolytic lesions at the DDC cause a marked reduction in stimulation-induced FLIR in certain forebrain, midbrain and brainstem regions that are activated by ICSS. Finally, the third article of the present thesis examines the role of the tVTA in brain stimulation reward and locomotor activity. Special attention was given to the behavioral functions of the glutamate receptors AMPA and NMDA, as well as the mu opioid receptors (MORs) expressed in the tVTA. Results show that pharmacological blockade of AMPA and NMDA receptors as well as activation of MORs in certain sites of the tVTA produce rewarding and locomotor stimulant effects. Results also show that downregulation of NMDA receptors in the tVTA using the small interfering RNA (siRNA) technique fails to alter brain stimulation reward, but causes a marked decrease in the maximal rate of operant responding for ICSS. The findings obtained from this thesis shed new light on the neural substrate underlying brain stimulation reward with respect to brain regions, connectivity, and neurotransmitter systems. They suggest that (i) the DDC constitutes a viable route for the transmission of brain stimulation reward and merges with the MFB on a common reward integrator, (ii) the DDC is functionally connected to forebrain, midbrain and brainstem regions that are activated by ICSS, and that (iii) glutamate and opioid transmission in the tVTA are major regulators of brain stimulation reward and locomotor activity. This work could have important implications for understanding appetitive behaviors, such as eating and drinking, and psychiatric conditions, such as substance use disorder, depression and schizophrenia.

Keyphrases: brain stimulation reward, dorsal diencephalic conduction system, intracranial self-stimulation, locomotor activity, tail of the ventral tegmental area