Hypothalamic Neurotensin Projections Promote Reward by Enhancing Glutamate Transmission in the VTA

Abstract

The lateral hypothalamus (LH) sends a dense glutamatergic and peptidergic projection to dopamine neurons in the ventral tegmental area (VTA), a cell group known to promote reinforcement and aspects of reward. The role of the LH to VTA projection in reward-seeking behavior can be informed by using optogenetic techniques to dissociate the actions of LH neurons from those of other descending forebrain inputs to the VTA. In the present study, we identify the effect of neurotensin (NT), one of the most abundant peptides in the LH to VTA projection, on excitatory synaptic transmission in the VTA and reward-seeking behavior. Mice displayed robust intracranial self-stimulation of LH to VTA fibers, an operant behavior mediated by NT 1 receptors (Nts1) and NMDA receptors. Whole-cell patch-clamp recordings of VTA dopamine neurons demonstrated that NT (10 nM) potentiated NMDA-mediated EPSCs via Nts1. Results suggest that NT release from the LH into the VTA activates Nts1, thereby potentiating NMDA-mediated EPSCs and promoting reward. The striking behavioral and electrophysiological effects of NT and glutamate highlight the LH to VTA pathway as an important component of reward.

Intracranial Self-Stimulation to Evaluate Abuse Potential of Drugs

“…1C). More recent studies have provided additional insight into this substrate by showing that self-stimulation can be maintained by optogenetic rather than electrical stimulation of glutamate/neurotensin-containing neurons that project from lateral hypothalamus to VTA dopamine (DA) neurons (Kempadoo et al, 2013). Conversely, stimulation of prefrontal cortex maintained self-stimulation by activating a different neural circuit that did not project through MFB.…”

“…Emerging optogenetic technologies permit targeted expression of channel rhodopsins in neurons of interest, and these neurons can then be selectively activated or inhibited by light stimuli delivered via fiber optic probes. ICSS maintained by light rather than electrical stimulation has been demonstrated (You et al, 2001;Kim et al, 2012;Kempadoo et al, 2013), and the potential of this technology for abuse potential testing remains to be determined.…”

Psychophysical inference of frequency-following fidelity in the neural substrate for brain stimulation reward

“…Nonetheless, it is reassuring that various candidates for the directly stimulated stage of the MFB substrate have been shown to support optical self-stimulation [65,72,73].…”

Possible contributions of a novel form of synaptic plasticity inAplysiato reward, memory, and their dysfunctions in mammalian brain

“…Like the L29 neurons, the VTA DA neurons are not homogenous and may be involved in learning about different types of USs (Lammel et al 2011(Lammel et al , 2012Navratilova et al 2012). They receive glutamatergic excitatory input from brain regions that process the CS (e.g., the PFC) and glutamatergic, cholinergic, and peptidergic excitatory input from regions that process the US (e.g., the laterodorsal and pedunculopontine tegmentum [PPTg] and lateral hypothalamus) (Floresco et al 2003;Aston-Jones et al 2010;Yeomans 2010;Zellner and Ranaldi 2010;Lammel et al 2012;Kempadoo et al 2013). During conditioning, the VTA DA neurons increase their firing to the CS and decrease their firing to the US, so that they fire in expectation of reward (Schultz et al 1997;Schultz 2011).…”