The ventral pallidum (VP) is a key component of the cortico-basal ganglia circuits that process motivational and emotional information, and also a crucial site for reward. Although the main targets of the two VP compartments, medial (VPm) and lateral (VPl) have already been established, the collateralization patterns of individual axons have not previously been investigated. Here we have fully traced eighty-four axons from VPm, VPl and the rostral extension of VP into the olfactory tubercle (VPr), using the anterograde tracer biotinylated dextran amine in the rat. Thirty to fifty percent of axons originating from VPm and VPr collateralized in the mediodorsal thalamic nucleus and lateral habenula, indicating a close association between the ventral basal ganglia-thalamo-cortical loop and the reward network at the single axon level. Additional collateralization of these axons in diverse components of the extended amygdala and corticopetal system supports a multisystem integration that may take place at the basal forebrain. Remarkably, we did not find evidence for a sharp segregation in the targets of axons arising from the two VP compartments, as VPl axons frequently collateralized in the caudal lateral hypothalamus and ventral tegmental area, the well-known targets of VPm, while VPm axons, in turn, also collateralized in typical VPl targets such as the subthalamic nucleus, substantia nigra pars compacta and reticulata, and retrorubral field. Nevertheless, VPl and VPm displayed collateralization patterns that paralleled those of dorsal pallidal components, confirming at the single axon level the parallel organization of functionally different basal ganglia loops.

The patterns of axonal collateralization of nucleus accumbens (Acb) projection neurons were investigated in the rat by means of single-axon tracing techniques using the anterograde tracer biotinylated dextran amine. Seventy-three axons were fully traced, originating from either the core (AcbC) or shell (AcbSh) compartment, as assessed by differential calbindin D28k-immunoreactivity. Axons from AcbC and AcbSh showed a substantial segregation in their targets; target areas were either exclusively or preferentially innervated from AcbC or AcbSh. Axon collaterals in the subthalamic nucleus were found at higher than expected frequencies; moreover, these originated exclusively in the dorsal AcbC. Intercompartmental collaterals were observed from ventral AcbC axons into AcbSh, and likewise, interconnections at pallidal and mesencephalic levels were also observed, although mostly from AcbC axons toward AcbSh targets, possibly supporting crosstalk between the two subcircuits at several levels. Cell somata giving rise to short-range accumbal axons, projecting to the ventral pallidum (VP), were spatially intermingled with others, giving rise to long-range axons that innervated VP and more caudal targets. This anatomical organization parallels that of the dorsal striatum and provides the basis for possible dual direct and indirect actions from a single axon on either individual or small sets of neurons.

Genetic microdeletion at the 22q11 locus is associated with very high risk for schizophrenia. The 22q11.2 microdeletion (Df(h22q11)/+) mouse model shows cognitive deficits observed in this disorder, some of which can be linked to dysfunction of the prefrontal cortex (PFC). We used behavioral (n = 10 per genotype), electrophysiological (n = 7 per genotype per group), and neuroanatomical (n = 5 per genotype) techniques to investigate schizophrenia-related pathology of Df(h22q11)/+ mice, which showed a significant decrease in the total number of parvalbumin positive interneurons in the medial PFC. The Df(h22q11)/+ mice when tested on PFC-dependent behavioral tasks, including gambling tasks, perform significantly worse than control animals while exhibiting normal behavior on hippocampus-dependent tasks. They also show a significant decrease in hippocampus-medial Prefrontal cortex (H-PFC) synaptic plasticity (long-term potentiation, LTP). Acute platform stress almost abolished H-PFC LTP in both wild-type and Df(h22q11)/+ mice. H-PFC LTP was restored to prestress levels by clozapine (3 mg/kg i.p.) in stressed Df(h22q11)/+ mice, but the restoration of stress-induced LTP, while significant, was similar between wild-type and Df(h22q11)/+ mice. A medial PFC dysfunction may underlie the negative and cognitive symptoms in human 22q11 deletion carriers, and these results are relevant to the current debate on the utility of clozapine in such subjects.