Medial Forebrain Bundle Lesions Fail to Structurally and Functionally Disconnect the Ventral Tegmental Area from Many Ipsilateral Forebrain Nuclei: Implications for the Neural Substrate of Brain Stimulation Reward

Abstract

Lesions in the medial forebrain bundle rostral to a stimulating electrode have variable effects on the rewarding efficacy of self-stimulation. We attempted to account for this variability by measuring the anatomical and functional effects of electrolytic lesions at the level of the lateral hypothalamus (LH) and by correlating these effects to postlesion changes in threshold pulse frequency (pps) for self-stimulation in the ventral tegmental area (VTA). We implanted True Blue in the VTA and compared cell labeling patterns in forebrain regions of intact and lesioned animals. We also compared stimulation-induced regional [14C]deoxyglucose (DG) accumulation patterns in the forebrains of intact and lesioned animals. As expected, postlesion threshold shifts varied: threshold pps remained the same or decreased in eight animals, increased by small but significant amounts in three rats, and increased substantially in six subjects. Unexpectedly, LH lesions did not anatomically or functionally disconnect all forebrain nuclei from the VTA. Most septal and preoptic regions contained equivalent levels of True Blue label in intact and lesioned animals. In both intact and lesioned groups, VTA stimulation increased metabolic activity in the fundus of the striatum (FS), the nucleus of the diagonal band, and the medial preoptic area. On the other hand, True Blue labeling demonstrated anatomical disconnection of the accumbens, FS, substantia innominata/magnocellular preoptic nucleus (SI/MA), and bed nucleus of the stria terminalis. [14C]DG autoradiography indicated functional disconnection of the lateral preoptic area and SI/MA. Correlations between patterns of True Blue labeling or [14C]deoxyglucose accumulation and postlesion shifts in threshold pulse frequency were weak and generally negative. These direct measures of connectivity concord with the behavioral measures in suggesting a diffuse net-like connection between forebrain nuclei and the VTA.

Endomorphin‐1 and ‐2 immunoreactive cells in the hypothalamus are labeled by fluoro‐gold injections to the ventral tegmental area

“…Reciprocal connections may also be present, based on evidence for efferent connections from the VTA to the posterior hypothalamus (Beckstead et al, 1979). These pathways may be part of diffuse "net-like" (rather than "cable-like") pathways associated with the MFB (Simmons et al, 1998) or separate reward pathways independent of the MFB (Phillips, 1984).…”

Regional neural activity within the substantia nigra during peri-ictal flurothyl generalized seizure stages

“…Deoxyglucose autoradiography-To examine functional neural activity (Sokoloff et al, 1977) over the entire 20 min studied, we injected the rats subcutaneously with 2 DG (0.05 μCi/g, Amersham) as described previously by others and us (Simmons et al, 1998;Velíšek et al, 2005). The advantage of the subcutaneous injection for seizure development studies is that uptake is continuous and therefore samples the entire post-injection time period compared to an i.v.…”

“…The advantage of the subcutaneous injection for seizure development studies is that uptake is continuous and therefore samples the entire post-injection time period compared to an i.v. bolus injection, which is more suitable for stable states (Simmons et al, 1998). In addition, the subcutaneous administration is less invasive compared to the intravenous injection, thus minimizing the stress of the animals.…”

The central extended amygdala network as a proposed circuit underlying reward valuation

“…To address this issue, Simmons et al (1998) implanted stimulating electrodes in the ventral tegmental MFB and made electrolytic lesions in the lateral hypothalamic area, then assessed the structural and functional integrity of the nucleus accumbens, the lateral septum, the diagonal band of Broca, the preoptic area, the substantia innominata (i.e. the sublenticular basal forebrain) and the bed nucleus of the stria terminalis.…”