Direct hypothalamic and indirect trans-pallidal, trans-thalamic, or trans-septal control of accumbens signaling and their roles in food intake

Abstract

Due in part to the increasing incidence of obesity in developed nations, recent research aims to elucidate neural circuits that motivate humans to overeat. Earlier research has described how the nucleus accumbens shell (AcbSh) motivates organisms to feed by activating neuronal populations in the lateral hypothalamus (LH). However, more recent research suggests that the LH may in turn communicate with the AcbSh, both directly and indirectly, to re-tune the motivation to consume foods with homeostatic and food-related sensory signals. Here, we discuss the functional and anatomical evidence for an LH to AcbSh connection and its role in eating behaviors. The LH appears to modulate Acb activity directly, using neurotransmitters such as hypocretin/orexin or melanin concentrating hormone (MCH). The LH also indirectly regulates AcbSh activity through certain subcortical "relay" regions, such as the lateral septum (LS), ventral pallidum (VP), and paraventricular thalamus, using a variety of neurotransmitters. This review aims to summarize studies on these topics and outline a model by which LH circuits processing energy balance can modulate AcbSh neural activity to regulate feeding behavior.

Keywords: accumbens; eating; lateral hypothalamus; paraventricular thalamus; septum; ventral pallidum.

Figure 1

Evidence for a feeding-specific connection between the AcbSh and the LH. Unilateral aAcbSh injection of the AMPA receptor antagonist DNQX (0.75 µg in 0.3 µL of a mixed DMSO-artificial CSF vehicle) significantly increases feeding. This feeding is suppressed by concurrent administration of D-AP5 (2 µg in 0.3 µL of artificial CSF) into the LH of the ipsilateral, but not contralateral, brain hemisphere. This figure was duplicated from a prior study (Urstadt et al., 2013a).

Figure 2

Morphine and DALA increase food intake significantly above controls when injected into the caudal LS but not into the nearby caudate putamen (CP) (panel A). MR-2034 did not significantly increase intake in either of these brain areas. Numbers at the base of each bar represent the number of animals used per group. A Nissl-stained section with an injection site into the the border of the caudal LS and septofimbrial area is shown in panel (B). These figure components were adapted from a prior study (Stanley et al., 1988).

Figure 3

Anterograde tract tracing evidence from various studies indicates an ascending trans-pallidal LH to AcbSh circuit in the rat brain. PHA-L-infiltrated neurons in the suprafornical LH (LHAs; panel A) and the anterior subfornical LH (LHAsfa; panel C) send moderate amounts of fibers to the amVP (panels B and D) (Goto et al., ; Hahn and Swanson, 2010). PHA-L-labeled neurons in the amVP (panel E) send projections to the anterior (panel F) and especially posterior (panel G) medial AcbSh (Groenewegen et al., 1993). Thus, the VP subregion receiving LH input projects in turn to the medial AcbSh. Abbreviations: BST—bed nucleus of the stria terminalis; cp—cerebral peduncle; fx—fornix; LHA—lateral hypothalamic area; LPO—lateral preoptic area; MPO—medial preoptic area; mt—mammillothalamic tract; NDB—diagonal band nucleus; och—optic chiasm; opt—optic tract; V3—third ventricle; VP—ventral pallidum; ZI—zona incerta.

Figure 4

Sagittal diagram of direct hypothalamic and indirect trans-pallidal, trans-thalamic, and trans-septal innervation of the AcbSh. Within a sagittal plane, the boxed region designates an area of the rat forebrain within which the regions of interest reside (top panel); this area is magnified to show sources of AcbSh innervation (bottom panel). Subregions of the LH area (LHA), the pfLH, lLH, and vlLH, project both directly to the AcbSh and to other regions that project onward to the AcbSh. Green lines indicate glutamatergic signals, red lines indicate GABAergic signals, and blue lines indicate mixed or neuropeptidergic signals. Circles indicate cell bodies. Line thickness denotes “strength” of connections. Such strengths were determined by amounts of anterogradely labeled fibers or retrogradely labeled cells observed in prior studies of each specific projection. This sagittal template was modified from a brain atlas (Paxinos and Watson, 2013). plAcbSh—posterolateral AcbSh.