Véronique Coizet

Subcortical loops through the basal ganglia

Parallel, largely segregated, closed-loop projections are an important component of cortical-basal ganglia-cortical connectional architecture. Here, we present the hypothesis that such loops involving the neocortex are neither novel nor the first evolutionary example of closed-loop architecture involving the basal ganglia. Specifically, we propose that a phylogenetically older, closed-loop series of subcortical connections exists between the basal ganglia and brainstem sensorimotor structures, a good example of which is the midbrain superior colliculus. Insofar as this organization represents a general feature of brain architecture, cortical and subcortical inputs to the basal ganglia might act independently, co-operatively or competitively to influence the mechanisms of action selection.

A direct projection from superior colliculus to substantia nigra for detecting salient visual events

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.

Nociceptive responses of midbrain dopaminergic neurones are modulated by the superior colliculus in the rat

Midbrain dopaminergic neurones exhibit a short-latency phasic response to unexpected, biologically salient stimuli. In the rat, the superior colliculus is critical for relaying short-latency visual information to dopaminergic neurones. Since both collicular and dopaminergic neurones are also responsive to noxious stimuli, we examined whether the superior colliculus plays a more general role in the transmission of short-latency sensory information to the ventral midbrain. We therefore tested whether the superior colliculus is a critical relay for nociceptive input to midbrain dopaminergic neurones. Simultaneous recordings were made from collicular and dopaminergic neurones in the anesthetized rat, during the application of noxious stimuli (footshock). Most collicular neurones exhibited a short-latency, short duration excitation to footshock. The majority of dopaminergic neurones (92/110; 84%) also showed a short-latency phasic response to the stimulus. Of these, 79/92 (86%) responded with an initial inhibition and the remaining 14/92 (14%) responded with an excitation. Response latencies of dopaminergic neurones were reliably longer than those of collicular neurones. Tonic suppression of collicular activity by an intracollicular injection of the local anesthetic lidocaine reduced the latency, increased the duration but reduced the magnitude of the phasic inhibitory dopaminergic response. These changes were accompanied by a decrease in the baseline firing rate of dopaminergic neurones. Activation of the superior colliculus by the local injections of the GABA(A) antagonist bicuculline also reduced the latency of inhibitory nociceptive responses of dopaminergic neurones, which was accompanied by an increased in baseline dopaminergic firing. Aspiration of the ipsilateral superior colliculus failed to alter the nociceptive response characteristics of dopaminergic neurones although fewer nociceptive neurones were encountered after the lesions. Together these results suggest that the superior colliculus can modulate both the baseline activity of dopaminergic neurones and their phasic responses to noxious events. However, the superior colliculus is unlikely to be the primary source of nociceptive sensory input to the ventral midbrain.

A direct projection from superior colliculus to substantia nigra pars compacta in the cat.

Dopaminergic neurons exhibit a short-latency, phasic response to unexpected, biologically salient stimuli. The midbrain superior colliculus also is sensitive to such stimuli, exhibits sensory responses with latencies reliably less than those of dopaminergic neurons, and, in rat, has been shown to send direct projections to regions of the substantia nigra and ventral tegmental area containing dopaminergic neurons (e.g. pars compacta). Recent electrophysiological and electrochemical evidence also suggests that tectonigral connections may be critical for relaying short-latency (<100 ms) visual information to midbrain dopaminergic neurons. By investigating the tectonigral projection in the cat, the present study sought to establish whether this pathway is a specialization of the rodent, or whether it may be a more general feature of mammalian neuroanatomy. Anterogradely and retrogradely transported anatomical tracers were injected into the superior colliculus and substantia nigra pars compacta, respectively, of adult cats. In the anterograde experiments, abundant fibers and terminals labeled with either biotinylated dextran amine or Phaseolus vulgaris leucoagglutinin were seen in close association with tyrosine hydroxylase-positive (dopaminergic) somata and processes in substantia nigra pars compacta and the ventral tegmental area. In the retrograde experiments, injections of biotinylated dextran amine into substantia nigra produced significant retrograde labeling of tectonigral neurons of origin in the intermediate and deep layers of the ipsilateral superior colliculus. Approximately half of these biotinylated dextran amine-labeled neurons were, in each case, shown to be immunopositive for the calcium binding proteins, parvalbumin or calbindin. Significantly, virtually no retrogradely labeled neurons were found either in the superficial layers of the superior colliculus or among the large tecto-reticulospinal output neurons. Taken in conjunction with recent data in the rat, the results of this study suggest that the tectonigral projection may be a common feature of mammalian midbrain architecture. As such, it may represent an additional route by which short-latency sensory information can influence basal ganglia function.

Phasic activation of substantia nigra and the ventral tegmental area by chemical stimulation of the superior colliculus: an electrophysiological investigation in the rat

The source of short‐latency visual input to midbrain dopaminergic (DA) neurons is not currently known; however, the superior colliculus (SC) is a subcortical visual structure which has response latencies consistently shorter than those recorded for DA neurons in substantia nigra and the ventral tegmental area. To test whether the SC represents a plausible route by which visual information may gain short latency access to the ventral midbrain, the present study examined whether experimental stimulation of the SC can influence the activity of midbrain DA neurons. In urethane‐anaesthetized rats, 63 pairs of extracellular recordings were obtained from neurons in the SC and ipsilateral ventral midbrain, before and after local disinhibitory injections of the GABA antagonist bicuculline (20–40 ng/200–400 nL saline) into the SC. Neurons recorded from substantia nigra and the ventral tegmental area were classified as putative DA (25/63, 39.7%) or putative non‐DA (38/63, 60.3%). In nearly half the cases (27/63, 42.8%), chemical stimulation of the SC evoked a corresponding increase in neural activity in the ventral midbrain. This excitatory effect did not distinguish between DA and non‐DA neurons. In 6/63 cases (9.5%), SC activation elicited a reliable suppression of activity, while the remaining 30/63 cases (47.6%) were unaffected. In almost a third of cases (16/57, 28.1%) intense phasic activation of the SC was associated with correlated phasic activation of neurons in substantia nigra and the ventral tegmental area. These data suggest that the SC is in a position to play an important role in discriminating the appropriate stimulus qualities required to activate DA cells at short latency.

Tectonigral Projections in the Primate: A Pathway for Pre-Attentive Sensory Input to Midbrain Dopaminergic Neurons

Much of the evidence linking the short‐latency phasic signaling of midbrain dopaminergic neurons with reward‐prediction errors used in learning and habit formation comes from recording the visual responses of monkey dopaminergic neurons. However, the information encoded by dopaminergic neuron activity is constrained by the qualities of the afferent visual signals made available to these cells. Recent evidence from rats and cats indicates the primary source of this visual input originates subcortically, via a direct tectonigral projection. The present anatomical study sought to establish whether a direct tectonigral projection is a significant feature of the primate brain. Injections of anterograde tracers into the superior colliculus of macaque monkeys labelled terminal arbors throughout the substantia nigra, with the densest terminations in the dorsal tier. Labelled boutons were found in close association (possibly indicative of synaptic contact) with ventral midbrain neurons staining positively for the dopaminergic marker tyrosine hydroxylase. Injections of retrograde tracer confined to the macaque substantia nigra retrogradely labelled small‐ to medium‐sized neurons in the intermediate and deep layers of the superior colliculus. Together, these data indicate that a direct tectonigral projection is also a feature of the monkey brain, and therefore likely to have been conserved throughout mammalian evolution. Insofar as the superior colliculus is configured to detect unpredicted, biologically salient, sensory events, it may be safer to regard the phasic responses of midbrain dopaminergic neurons as ‘sensory prediction errors’ rather than ‘reward prediction errors’, in which case dopamine‐based theories of reinforcement learning will require revision.

Short-Latency Visual Input to the Subthalamic Nucleus Is Provided by the Midbrain Superior Colliculus

The subthalamic nucleus (STN) is one of the principal input nuclei of the basal ganglia. Using electrophysiological techniques in anesthetized rats, we show that the STN becomes responsive to visual stimuli at short latencies when local disinhibitory injections are made into the midbrain superior colliculus (SC), an important subcortical visual structure. Significantly, only injections into the lateral, but not medial, deep layers of the SC were effective. Corresponding disinhibition of primary visual cortex also was ineffective. Complementary anatomical analyses revealed a strong, regionally specific projection from the deep layers of the lateral SC to neurons in rostral and dorsal sectors of the STN. Given the retinocentric organization of the SC, these results suggest that lower-field stimuli represented in the lateral colliculus have a direct means of communicating with the basal ganglia via the STN that is not afforded to visual events occurring in the upper visual field.

Interactions between the Midbrain Superior Colliculus and the Basal Ganglia

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.

The parabrachial nucleus is a critical link in the transmission of short latency nociceptive information to midbrain dopaminergic neurons

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.

Collateralization of the tectonigral projection with other major output pathways of superior colliculus in the rat

Dopaminergic (DA) neurons exhibit a short‐latency, phasic response to unexpected, biologically salient stimuli. The superior colliculus (SC) is also sensitive to such stimuli and sends a projection directly to DA‐containing regions of the ventral midbrain. Recent evidence suggests that the SC is a critical relay for transmitting short‐latency visual information to DA neurons. An important question is whether the ventral midbrain is an exclusive target of tectonigral neurons, or whether the tectonigral projection is a collateral branch of other tectofugal pathways. Double‐label retrograde anatomical tracing techniques were used to address this issue. Injections of either Diamidino Yellow or Fluorogold into substantia nigra pars compacta (SNc) were combined with larger injections of True Blue into one of the following efferent projections of the SC: 1) target regions of the ipsilateral ascending projection to the thalamus; 2) the crossed descending tecto‐reticulo‐spinal pathway; 3) target structures of the ipsilateral descending projection; and 4) the contralateral superior colliculus. Moderate numbers of double‐labeled neurons were observed following combined injections into substantia nigra and individual nuclei in the thalamus (ventromedial nucleus, 21.3%; central lateral, 18.4%; parafasicular nucleus 6.0%). Much less double‐labeling was associated with injections into either of the descending projections (crossed, 1.0–3.2%; uncrossed, 0.2–2.7%) or the contralateral SC (0.7–1.9%). These results suggest: i) the SC may provide a coordinated input concerning the occurrence of unpredicted sensory events to both the substantia nigra and striatum (via the thalamus); and ii) few gaze‐related motor signals are simultaneously relayed to DA‐containing regions of the ventral midbrain. J. Comp. Neurol. 500:1034–1049, 2007.