UCSF

The lateral hypothalamus (LH) is a brain region that provides one of the largest sources of glutamatergic and peptidergic input to the ventral tegmental area (VTA). Electrical stimulation in this area produces reward, however, the medial forebrain bundle courses through the LH. Therefore, understanding the role of the LH to VTA projection in mediating reward-related behavior and pathological states of reward-seeking such as drug abuse can be informed by separating the role of LH neurons from other descending forebrain inputs to the VTA. In the present study, we focus on the action of neurotensin (NT), one of the most abundant peptides in the LH to VTA projection, on excitatory synaptic transmission in the VTA and its relevance in goal-directed behavior. Whole-cell patch clamp techniques in midbrain slices of C57Bl/6 mice were used to demonstrate that NT potentiates NMDA-mediated excitatory postsynaptic currents (EPSCs) via the NT 1 receptor (Nts1). NT release at optogenetically-isolated LH-VTA terminals indicates synapse-specific effects ex vivo. Using in vivo optogenetic techniques, we demonstrate that animals display robust intracranial self-stimulation of lateral hypothalamic terminals in the VTA. This behavior is significantly attenuated by blockade of either Nts1 or NDMA receptors in the VTA. The striking behavioral and electrophysiological effects of lateral hypothalamic NT in the VTA highlight this pathway as an important component in mediating reward-related behavior.