Elaborating the connections of a closed-loop forebrain circuit in the rat: Circumscribed evidence for novel topography within a cortico-striato-pallidal triple descending projection, with thalamic feedback, to the anterior lateral hypothalamic area.

Unlabelled: Motivated behaviors are regulated by distributed forebrain networks. Traditional approaches have often focused on individual brain regions and connections that do not capture the topographic organization of forebrain connectivity. We performed co-injections of anterograde and retrograde tract tracers in rats to provide novel high-spatial resolution evidence of topographic connections that elaborate a previously identified closed-loop forebrain circuit implicated in affective and motivational processes. The nodes of this circuit include select regions of the medial prefrontal cortex (defined here more specifically as the cingulate region, CNG), a dorsomedial portion of the nucleus accumbens (ACBdm), a portion of the medial substantia innominata (SIm), and the anterior lateral hypothalamic area (LHAa). The circuit also reportedly receives a feedback loop from the anterior region of the paraventricular thalamic nucleus (PVTa). In this draft report, we provide detailed circumscribed evidence supporting these regions as interconnected nodes, and provide several novel findings concerning the topographic organization of their projections. First, we identified the ACBdm based on its unique connectivity. Anterograde labeling from anterior paraventricular thalamic nucleus (PVTa) and retrograde labeling from medial substantia innominata (SIm) and lateral hypothalamic area (LHA) were restricted to the dorsomedial ACB (ACBdm). Strikingly, this labeling formed a longitudinal column extending along virtually the entire anteroposterior axis of ACBdm. Subsequent analysis revealed a convergence of ACBdm axon terminals and retrogradely labeled neurons from LHA within the anterior SIm. Furthermore, we identified cortical CNG regions related to this circuit. These regions contained retrograde labeling from both ACBdm and LHA, and anterograde labeling from PVTa. These cortical subdomains included regions previously implicated in the circuit but for which detailed organization has been unknown: (1) a region between the posterior prelimbic and infralimbic areas; (2) posterior part of basolateral and basomedial amygdalar nuclei, and (3) anterior pole of ventral subiculum. Our circumscribed findings, which await additional samples and analysis, support the existence of a topographically organized closed-loop circuit and identify two additional novel features: (1) direct evidence for an elaborate for a cortico-striato-pallidal motif comprising a triple descending projection to the LHA via direct, indirect, and "hyperdirect" pathways, and (2) a thalamic feedback system with specific projections to of the circuit. We discuss the implications of this newly elaborated circuit for understanding the neural basis of motivational processes.

Significance Statement: We used a bottom-up approach to identify a distinct longitudinal column of dorsomedial nucleus accumbens (ACBdm) that spans its anteroposterior axis. This region projects to medial substantia innominata (SIm) and lateral hypothalamic area (LHA), resembling the "direct" and "indirect" pathways of the classical basal ganglia circuit. We also identified topographically distinct regions in medial prefrontal cortex (strictly delineated here as the cingulate region, CNG), ventral subiculum (SUBv), and basolateral amygdala (BLA) that project to both ACBdm and LHA, further defining the circuit. Finally, we identified an LHA-to-anterior paraventricular thalamic nucleus (PVTa) feedback projection that selectively targets cortical and striatal nodes within the circuit. Our work provides novel detailed maps that bolster the proposal that this "triple descending projection" (cortico-striato-pallidal) and associated thalamic feedback loop play a role in affective and motivational processes.