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Midbrain dopaminergic neurons respond to unexpected and biologically salient events, but little is known about the sensory systems underlying this response. Here we describe, in the rat, a direct projection from a primary visual structure, the midbrain superior colliculus (SC), to the substantia nigra pars compacta (SNc) where direct synaptic contacts are made with both dopaminergic and non-dopaminergic neurons. Complementary electrophysiological data reveal that short-latency visual responses in the SNc are abolished by ipsilateral lesions of the SC and increased by local collicular stimulation. These results show that the tectonigral projection is ideally located to relay short-latency visual information to dopamine-containing regions of the ventral midbrain. We conclude that it is within this afferent sensory circuitry that the critical perceptual discriminations that identify stimuli as both unpredicted and biologically salient are made.

Unexpected, biologically salient stimuli elicit a short-latency, phasic response in midbrain dopaminergic (DA) neurons. Although this signal is important for reinforcement learning, the information it conveys to forebrain target structures remains uncertain. One way to decode the phasic DA signal would be to determine the perceptual properties of sensory inputs to DA neurons. After local disinhibition of the superior colliculus in anesthetized rats, DA neurons became visually responsive, whereas disinhibition of the visual cortex was ineffective. As the primary source of visual afferents, the limited processing capacities of the colliculus may constrain the visual information content of phasic DA responses.

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An important component of the architecture of cortico-basal ganglia connections is the parallel, re-entrant looped projections that originate and return to specific regions of the cerebral cortex. However, such loops are unlikely to have been the first evolutionary example of a closed-loop architecture involving the basal ganglia. A phylogenetically older, series of subcortical loops can be shown to link the basal ganglia with many brainstem sensorimotor structures. While the characteristics of individual components of potential subcortical re-entrant loops have been documented, the full extent to which they represent functionally segregated parallel projecting channels remains to be determined. However, for one midbrain structure, the superior colliculus (SC), anatomical evidence for closed-loop connectivity with the basal ganglia is robust, and can serve as an example against which the loop hypothesis can be evaluated for other subcortical structures. Examination of ascending projections from the SC to the thalamus suggests there may be multiple functionally segregated systems. The SC also provides afferent signals to the other principal input nuclei of the basal ganglia, the dopaminergic neurones in substantia nigra and to the subthalamic nucleus. Recent electrophysiological investigations show that the afferent signals originating in the SC carry important information concerning the onset of biologically significant events to each of the basal ganglia input nuclei. Such signals are widely regarded as crucial for the proposed functions of selection and reinforcement learning with which the basal ganglia have so often been associated.

Many dopaminergic neurons exhibit a short-latency response to noxious stimuli, the source of which is unknown. Here we report that the nociceptive-recipient parabrachial nucleus appears to be a critical link in the transmission of pain related information to dopaminergic neurons. Injections of retrograde tracer into the substantia nigra pars compacta of the rat labelled neurons in both the lateral and medial parts of the parabrachial nucleus, and intra-parabrachial injections of anterograde tracers revealed robust projections to the pars compacta and ventral tegmental area. Axonal boutons were seen in close association with tyrosine hydroxylase-positive (presumed dopaminergic) and negative elements in these regions. Simultaneous extracellular recordings were made from parabrachial and dopaminergic neurons in the anaesthetized rat, during the application of noxious footshock. Parabrachial neurons exhibited a short-latency, short duration excitation to footshock while dopaminergic neurons exhibited a short-latency inhibition. Response latencies of dopaminergic neurons were reliably longer than those of parabrachial neurons. Intra-parabrachial injections of the local anasethetic lidocaine or the GABAA receptor antagonist muscimol reduced tonic parabrachial activity and the amplitude (and in the case of lidocaine, duration) of the phasic response to footshock. Suppression of parabrachial activity with lidocaine reduced the baseline firing rate of dopaminergic neurons, while both lidocaine and muscimol reduced the amplitude of the phasic inhibitory response to footshock, in the case of lidocaine sometimes abolishing it altogether. Considered together, these results suggest that the parabrachial nucleus is an important source of short-latency nociceptive input to the dopaminergic neurons.

The insular cortex (INS) is extensively connected to the central nucleus of the amygdala (CEA), and both regions send convergent projections into the caudal lateral hypothalamus (LHA) encompassing the parasubthalamic nucleus (PSTN). However, the organization of the network between these structures has not been clearly delineated in the literature, although there has been an upsurge in functional studies related to these structures, especially with regard to the cognitive and psychopathological control of feeding. We conducted tract-tracing experiments from the INS and observed a pathway to the PSTN region that runs parallel to the canonical hyperdirect pathway from the isocortex to the subthalamic nucleus (STN) adjacent to the PSTN. In addition, an indirect pathway with a relay in the central amygdala was also observed that is similar in its structure to the classic indirect pathway of the basal ganglia that also targets the STN. C-Fos experiments showed that the PSTN complex reacts to neophobia and sickness induced by lipopolysaccharide or cisplatin. Chemogenetic (designer receptors exclusively activated by designer drugs [DREADD]) inhibition of tachykininergic neurons (Tac1) in the PSTN revealed that this nucleus gates a stop “no-eat” signal to refrain from feeding when the animal is subjected to sickness or exposed to a previously unknown source of food. Therefore, our anatomical findings in rats and mice indicate that the INS-PSTN network is organized in a similar manner as the hyperdirect and indirect basal ganglia circuitry. Functionally, the PSTN is involved in gating feeding behavior, which is conceptually homologous to the motor no-go response of the adjacent STN.

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