Distinct Neuromodulatory Effects of Endogenous Orexin and Dynorphin Corelease on Projection-Defined Ventral Tegmental Dopamine Neurons

LHA (Lateral hypothalamic area) MBA:194 functionally connects to VTA (Ventral tegmental area) MBA:749 · Mouse

In VTA dopamine neurons retrogradely labelled from the basolateral amygdala, photostimulation of lateral hypothalamic orexin/dynorphin terminals suppressed evoked firing in two-thirds of cells, an effect blocked by the kappa-opioid antagonist NorBNI; a small, statistically non-significant increase occurred in a quarter of cells, and no change remained when both orexin-1 and kappa-opioid antagonists were present.

Fig. 7D–K

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VTA (Ventral tegmental area) MBA:749 projects to BLA (Basolateral amygdalar nucleus) MBA:295 · Mouse

RetroBeads placed in the basolateral amygdala labelled tyrosine hydroxylase-positive ventral tegmental area neurons, identifying a VTA dopaminergic projection to the BLA.

Fig. 7A,C

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VTA (Ventral tegmental area) MBA:749 projects to ACB (Nucleus accumbens) MBA:56 · Mouse

Red RetroBeads injected into either the lateral or the medial shell of the nucleus accumbens retrogradely labelled tyrosine hydroxylase-positive neurons in the ventral tegmental area, which were then recorded in slices.

Figs. 5A,C and 6A,C

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LHA (Lateral hypothalamic area) MBA:194 functionally connects to VTA (Ventral tegmental area) MBA:749 · Mouse

Attempts to evoke fast AMPA receptor-mediated excitatory postsynaptic currents in VTA neurons by optical stimulation of lateral hypothalamic orexin/dynorphin terminals failed; no light-evoked AMPA currents were detected at -70 mV.

Extended Data Fig. 2-1

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LHA (Lateral hypothalamic area) MBA:194 functionally connects to VTA (Ventral tegmental area) MBA:749 · Mouse

Photostimulation (30 Hz, up to 30 s) of channelrhodopsin-expressing lateral hypothalamic orexin/dynorphin terminals in slices bidirectionally changed evoked firing of tyrosine hydroxylase-positive VTA neurons: some cells fired more, others less, and a minority were unaffected. The increases persisted with glutamate and GABA-A blockers and were reversed by the orexin-1 receptor antagonist SB334867, the decreases were reversed by the kappa-opioid antagonist NorBNI, and combined antagonists abolished any change, indicating peptidergic (orexin and dynorphin) postsynaptic modulation rather than fast transmission.

Figs. 1G–M, 2, 3

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LHA (Lateral hypothalamic area) MBA:194 projects to VTA (Ventral tegmental area) MBA:749 · Mouse

Cre-dependent ChR2-mCherry expressed in orexin neurons of the lateral hypothalamus of orexin-cre mice (81% of LH orexin cells labelled, 91% of labelled cells orexin-positive) produced mCherry-labelled axonal fibres visible within the ventral tegmental area alongside tyrosine hydroxylase-positive neurons.

Fig. 1C,E

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LHA (Lateral hypothalamic area) MBA:194 functionally connects to VTA (Ventral tegmental area) MBA:749 · Mouse

In VTA dopamine neurons retrogradely labelled from the medial accumbens shell, photostimulation of lateral hypothalamic orexin/dynorphin terminals raised evoked firing in a minority of cells (orexin-1 receptor dependent) and lowered it in the majority (kappa-opioid receptor dependent); two cells did not respond and the effects were absent with both antagonists applied.

Fig. 6D–K

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LHA (Lateral hypothalamic area) MBA:194 functionally connects to VTA (Ventral tegmental area) MBA:749 · Mouse

In VTA dopamine neurons retrogradely labelled from the lateral accumbens shell, optical stimulation of lateral hypothalamic orexin/dynorphin terminals increased evoked firing in most cells (reversed by the orexin-1 receptor antagonist) and decreased it in a smaller group (reversed by the kappa-opioid antagonist); one cell was unchanged and no effect remained when both antagonists were present.

Fig. 5D–K

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