The lateral preoptic area and ventral pallidum embolden behavior.

While recently completing a study of the effects of stimulating the lateral preoptic area (LPO) and ventral pallidum (VP) on locomotion and other movements, we also noticed LPO and VP effects on motivational drive and threat tolerance. Here, we have investigated these latter effects by testing conditioned place preference (CPP), behavior on the elevated plus maze (EPM) and the willingness of sated rats to occupy a harshly lit open field center to acquire sweet pellets, a measure of threat tolerance, following infusions of vehicle or bicuculline (bic) into the LPO and VP. LPO-bic infusions robustly increased total locomotion, and, in direct proportion, occupancy of both the harshly lit field center and open arms of the EPM. LPO bic also generated CPP, but did not increase sweet pellet ingestion. These effects were attenuated by dopamine D1 and D2 receptor antagonists, whether given individually or as a cocktail and systemically or infused bilaterally into the nucleus accumbens. VP-bic infusions did not increase total locomotion, but preferentially increased field center occupancy. VP-bic-infused rats compulsively ingested sweet pellets and did so even under the spotlight, whereas harsh illumination suppressed pellet ingestion in the control groups. VP bic produced CPP and increased open arm occupancy on the EPM. These effects were attenuated by pretreatment with dopamine receptor antagonists given systemically or as bilateral infusions into the VP, except for % distance in the field center (by D1 or D2 antagonists) and pellet ingestion (by D1 antagonist). Thus, boldness generated in association with LPO activation is tightly tied to locomotor activation and, as is locomotion itself, strongly DA dependent, whereas that accompanying stimulation of the VP is independent of locomotor activation and, at least in part, DA signaling. Furthermore, respective emboldened behaviors elicited from neither LPO nor VP could clearly be attributed to goal pursuit. Rather, emboldening of behavior seems more to be a fixed action response not fundamentally different than previously for reported locomotion, pivoting, backing, gnawing, and eating elicited by basal forebrain stimulation.

Lateral preoptic and ventral pallidal roles in locomotion and other movements.

The lateral preoptic area (LPO) and ventral pallidum (VP) are structurally and functionally distinct territories in the subcommissural basal forebrain. It was recently shown that unilateral infusion of the GABAA receptor antagonist, bicuculline, into the LPO strongly invigorates exploratory locomotion, whereas bicuculline infused unilaterally into the VP has a negligible locomotor effect, but when infused bilaterally, produces vigorous, abnormal pivoting and gnawing movements and compulsive ingestion. This study was done to further characterize these responses. We observed that bilateral LPO infusions of bicuculline activate exploratory locomotion only slightly more potently than unilateral infusions and that unilateral and bilateral LPO injections of the GABAA receptor agonist muscimol potently suppress basal locomotion, but only modestly inhibit locomotion invigorated by amphetamine. In contrast, unilateral infusions of muscimol into the VP affect basal and amphetamine-elicited locomotion negligibly, but bilateral VP muscimol infusions profoundly suppress both. Locomotor activation elicited from the LPO by bicuculline was inhibited modestly and profoundly by blockade of dopamine D2 and D1 receptors, respectively, but was not entirely abolished even under combined blockade of dopamine D1 and D2 receptors. That is, infusing the LPO with bic caused instances of near normal, even if sporadic, invigoration of locomotion in the presence of saturating dopamine receptor blockade, indicating that LPO can stimulate locomotion in the absence of dopamine signaling. Pivoting following bilateral VP bicuculline infusions was unaffected by dopamine D2 receptor blockade, but was completely suppressed by D1 receptor blockade. The present results are discussed in a context of neuroanatomical and functional organization underlying exploratory locomotion and adaptive movements.

Comparison of the locomotor-activating effects of bicuculline infusions into the preoptic area and ventral pallidum.

Ambulatory locomotion in the rodent is robustly activated by unilateral infusions into the basal forebrain of type A gamma-aminobutyric acid receptor antagonists, such as bicuculline and picrotoxin. The present study was carried out to better localize the neuroanatomical substrate(s) underlying this effect. To accomplish this, differences in total locomotion accumulated during a 20-min test period following bicuculline versus saline infusions in male Sprague-Dawley rats were calculated, rank ordered and mapped on a diagram of basal forebrain transposed from immunoprocessed sections. The most robust locomotor activation was elicited by bicuculline infusions clustered in rostral parts of the preoptic area. Unilateral infusions of bicuculline into the ventral pallidum produced an unanticipatedly diminutive activation of locomotion, which led us to evaluate bilateral ventral pallidal infusions, and these also produced only a small activation of locomotion, and, interestingly, a non-significant trend toward suppression of rearing. Subjects with bicuculline infused bilaterally into the ventral pallidum also exhibited persistent bouts of abnormal movements. Bicuculline infused unilaterally into other forebrain structures, including the bed nucleus of stria terminalis, caudate-putamen, globus pallidus, sublenticular extended amygdala and sublenticular substantia innominata, did not produce significant locomotor activation. Our data identify the rostral preoptic area as the main substrate for the locomotor-activating effects of basal forebrain bicuculline infusions. In contrast, slight activation of locomotion and no effect on rearing accompanied unilateral and bilateral ventral pallidal infusions. Implications of these findings for forebrain processing of reward are discussed.

Protracted maturation of forebrain afferent connections of the ventral tegmental area in the rat.

The mesocorticolimbic dopamine system has long attracted the interest of researchers concerned with the unique gamut of behavioral and mental health vulnerabilities associated with adolescence. Accordingly, the development of the mesocorticolimbic system has been studied extensively, but almost exclusively with regard to dopaminergic output, particularly in the nucleus accumbens and medial prefrontal cortex. To the contrary, the ontogeny of inputs to the ventral tegmental area (VTA), the source of mesocorticolimbic dopamine, has been neglected. This is not a trivial oversight, as the activity of VTA neurons, which reflects their capacity to transmit information about salient events, is sensitively modulated by inputs. Here, we assessed the development of VTA afferent connections using the ß subunit of cholera toxin (Ctß) as a retrograde axonal tracer in adolescent (postnatal day 39) and early adult (8-9-week-old) rats. After intra-VTA injections of Ctß, adolescent and early adult animals exhibited qualitatively similar distributions of retrogradely labeled neurons in the sense that VTA-projecting neurons were present at all of the same rostrocaudal levels in all of the same structures in both age groups. However, quantitation of retrogradely labeled neurons revealed that adolescent brains, compared with early adult brains, had significantly fewer VTA-projecting neurons preferentially within an interconnected network of cortical and striatopallidal forebrain structures. These findings provide a novel perspective on the development of the mesocorticolimbic dopamine system and may have important implications for age-dependent specificity in the function of this system, particularly with regard to adolescent impulsivity and mental health vulnerabilities.

On lateral septum-like characteristics of outputs from the accumbal hedonic "hotspot" of Peciña and Berridge with commentary on the transitional nature of basal forebrain "boundaries".

Peciña and Berridge (2005; J Neurosci 25:11777-11786) observed that an injection of the µ-opioid receptor agonist DAMGO (D-ala(2) -N-Me-Phe(4) -Glycol(5) -enkephalin) into the rostrodorsal part of the accumbens shell (rdAcbSh) enhances expression of hedonic "liking" responses to the taste of an appetitive sucrose solution. Insofar as the connections of this hedonic "hotspot" were not singled out for special attention in the earlier neuroanatomical literature, we undertook to examine them. We observed that the patterns of inputs and outputs of the rdAcbSh are not qualitatively different from those of the rest of the Acb, except that outputs from the rdAcbSh to the lateral preoptic area and anterior and lateral hypothalamic areas are anomalously robust and overlap extensively with those of the lateral septum. We also detected reciprocal interconnections between the rdAcbSh and lateral septum. Whether and how these connections subserve hedonic impact remains to be learned, but these observations lead us to hypothesize that the rdAcbSh represents a basal forebrain transition area, in the sense that it is invaded by neurons of the lateral septum, or possibly transitional neuronal forms sharing properties of both structures. We note that the proposed transition zone between lateral septum and rdAcbSh would be but one of many in the basal forebrain and conclude by reiterating the longstanding argument that the transitional nature of such boundary areas has functional importance, of which the precise nature will remain elusive until the neurophysiological and neuropharmacological implications of such zones of transition are more generally acknowledged and better addressed.

Inputs to the midbrain dopaminergic complex in the rat, with emphasis on extended amygdala-recipient sectors.

The midbrain dopaminergic neuronal groups A8, A9, A10, and A10dc occupy, respectively, the retrorubral field (RRF), substantia nigra compacta (SNc), ventral tegmental area (VTA), and ventrolateral periaqueductal gray (PAGvl). Collectively, these structures give rise to a mixed dopaminergic and nondopaminergic projection system that essentially permits adaptive behavior. However, knowledge is incomplete regarding how the afferents of these structures are organized. Although the VTA is known to receive numerous afferents from cortex, basal forebrain, and brainstem and the SNc is widely perceived as receiving inputs mainly from the striatum, the afferents of the RRF and PAGvl have yet to be assessed comprehensively. This study was performed to provide an account of those connections and to seek a better understanding of how afferents might contribute to the functional interrelatedness of the VTA, SNc, RRF, and PAGvl. Ventral midbrain structures received injections of retrograde tracer, and the resulting retrogradely labeled structures were targeted with injections of anterogradely transported Phaseolus vulgaris leucoagglutinin. Whereas all injections of retrograde tracer into the VTA, SNc, RRF, or PAGvl produced labeling in many structures extending from the cortex to caudal brainstem, pronounced labeling of structures making up the central division of the extended amygdala occurred following injections that involved the RRF and PAGvl. The anterograde tracing supported this finding, and the combination of retrograde and anterograde labeling data also confirmed reports from other groups indicating that the SNc receives robust input from many of the same structures that innervate the VTA, RRF, and PAGvl.