Paul G. Overton

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.

Stimulation of the prefrontal cortex in the rat induces patterns of activity in midbrain dopaminergic neurons which resemble natural burst events.

Evidence suggests that excitatory amino acid‐containing afferents from the prefrontal cortex (PFC) play an important role in the induction of burst firing in midbrain dopaminergic (DA) neurons. In the present study, the extracellular activity of individual DA neurons (A10 and A9 cell groups) was recorded during single pulse electrical stimulation (0.25 and 1 mA) of the PFC. The majority of cells were responsive, and two main patterns of activity were elicited: responses characterised by an initial excitation (E responses; 41.8% of responses at 0.25 mA and 26.6% at 1 mA; cell groups combined) and responses characterised by excitation following an initial inhibition (IE responses; 43.3% of responses at 0.25 mA and 56.6% at 1 mA; cell groups combined). Burst analysis performed on the excitatory phase of E and IE responses revealed that the excitation contained events which fulfilled the criteria for natural bursts in DA neurons. A procedure was developed for assessing whether these bursts were time‐locked to the stimulus. This showed that 27.9% of E responses and 33.3% of IE responses were accompanied by time‐locked bursts (currents and cell groups combined). It is argued that time‐locked bursts during IE responses were produced by rebound activation of a low threshold calcium conductance, whereas time‐locked bursts during E responses were produced by excitatory afferents. Since natural bursts in DA neurons also seem to involve cortically induced excitation, the hypothesis that the PFC plays a role in the production of natural bursts in DA neurons is strengthened.

Long-term potentiation at excitatory amino acid synapses on midbrain dopamine neurons.

Evidence suggests that a process analogous to long-term potentiation (LTP) may underlie the enhanced behavioural responses attending chronic administration of amphetamine and cocaine in animals (behavioural sensitization). Augmented excitatory amino acid (EAA)-mediated transmission at the level of midbrain dopamine neurons has been implicated as a change critical to the development of sensitization. Here we provide an initial demonstration that EAA synapses on dopamine neurons can undergo plasticity. Tetanic stimulation of the subthalamic nucleus induced a long-lasting increase (39.2 +/- 10.4%) in the amplitude of excitatory postsynaptic potentials recorded in dopamine neurons of the substantia nigra. This LTP, which did not occur in the presence of NMDA antagonists, may constitute the mechanism that lies at the heart of sensitization.

Antagonism of NMDA receptors but not AMPA/kainate receptors blocks bursting in dopaminergic neurons induced by electrical stimulation of the prefrontal cortex

SummaryEvidence suggests that the prefrontal cortex (PFC) plays an important role in the burst activity of midbrain dopaminergic (DA) neurons. In particular, electrical stimulation of the PFC elicits patterns of activity in DA neurons, closely time-locked to the stimulation, which resemble natural bursts. Given that natural bursts are produced by the activity of excitatory amino acid (EAA)-ergic afferents, if PFC-induced time-locked bursts are homologues of natural bursts, EAA antagonists should attenuate them. Hence, the NMDA (N-methy1-D-aspartate) antagonist CPP (3-((±)-2-carboxypiperazin-4-yl)propyl-1-phosphonic acid) and the AMPA (D,L-α-amino-3-hydroxy-5-methyl-4-isoxalone propionic acid)/kainate antagonist CNQX (6-cyano-7-nitroquinoxaline-2,3-dione) were applied by iontophoresis to DA neurons exhibiting time-locked bursts during PFC stimulation. CPP produced a significant reduction in time-locked bursting. In contrast, CNQX (at currents which antagonised AMPA responses) did not. These effects of CPP and CNQX on time-locked bursting mirror the effects previously reported for these drugs on natural bursting. Since natural bursting and bursting induced by PFC stimulation are both blocked selectively by CPP, the present results increase the degree of analogy between the two burst phenomena, thereby adding extra support to the contention that the cortex is involved in producing the natural bursting in DA neurons.

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.

Segregated Anatomical Input to Sub-Regions of the Rodent Superior Colliculus Associated with Approach and Defense

The superior colliculus (SC) is responsible for sensorimotor transformations required to direct gaze toward or away from unexpected, biologically salient events. Significant changes in the external world are signaled to SC through primary multisensory afferents, spatially organized according to a retinotopic topography. For animals, where an unexpected event could indicate the presence of either predator or prey, early decisions to approach or avoid are particularly important. Rodents’ ecology dictates predators are most often detected initially as movements in upper visual field (mapped in medial SC), while appetitive stimuli are normally found in lower visual field (mapped in lateral SC). Our purpose was to exploit this functional segregation to reveal neural sites that can bias or modulate initial approach or avoidance responses. Small injections of Fluoro-Gold were made into medial or lateral sub-regions of intermediate and deep layers of SC (SCm/SCl). A remarkable segregation of input to these two functionally defined areas was found. (i) There were structures that projected only to SCm (e.g., specific cortical areas, lateral geniculate and suprageniculate thalamic nuclei, ventromedial and premammillary hypothalamic nuclei, and several brainstem areas) or SCl (e.g., primary somatosensory cortex representing upper body parts and vibrissae and parvicellular reticular nucleus in the brainstem). (ii) Other structures projected to both SCm and SCl but from topographically segregated populations of neurons (e.g., zona incerta and substantia nigra pars reticulata). (iii) There were a few brainstem areas in which retrogradely labeled neurons were spatially overlapping (e.g., pedunculopontine nucleus and locus coeruleus). These results indicate significantly more structures across the rat neuraxis are in a position to modulate defense responses evoked from SCm, and that neural mechanisms modulating SC-mediated defense or appetitive behavior are almost entirely segregated.

Neurovascular coupling is brain region-dependent

Despite recent advances in alternative brain imaging technologies, functional magnetic resonance imaging (fMRI) remains the workhorse for both medical diagnosis and primary research. Indeed, the number of research articles that utilise fMRI have continued to rise unabated since its conception in 1991, despite the limitation that recorded signals originate from the cerebral vasculature rather than neural tissue. Consequently, understanding the relationship between brain activity and the resultant changes in metabolism and blood flow (neurovascular coupling) remains a vital area of research. In the past, technical constraints have restricted investigations of neurovascular coupling to cortical sites and have led to the assumption that coupling in non-cortical structures is the same as in the cortex, despite the lack of any evidence. The current study investigated neurovascular coupling in the rat using whole-brain blood oxygenation level-dependent (BOLD) fMRI and multi-channel electrophysiological recordings and measured the response to a sensory stimulus as it proceeded through brainstem, thalamic and cortical processing sites - the so-called whisker-to-barrel pathway. We found marked regional differences in the amplitude of BOLD activation in the pathway and non-linear neurovascular coupling relationships in non-cortical sites. The findings have important implications for studies that use functional brain imaging to investigate sub-cortical function and caution against the use of simple, linear mapping of imaging signals onto neural activity.

Chronic administration of (+)-amphetamine alters the reactivity of midbrain dopaminergic neurons to prefrontal cortex stimulation in the rat

Repeated intermittent administration of (+)-amphetamine produces sensitisation to many of the behavioural effects of the drug. Evidence suggests that excitatory amino acidergic projections from the prefrontal cortex (PFC) to dopaminergic (DA) neurons in the ventral midbrain may be partly involved in the maintenance of sensitisation once induced. The present study was designed to investigate whether chronic amphetamine administration produces any alteration to this input, by assessing the impact of single pulse electrical stimulation of the PFC (0.25 and 0.5 mA) on the extracellular activity of individual midbrain DA neurons in drug and vehicle treated rats. Animals were administered amphetamine according to a schedule known to produce sensitisation (2.5 mg/kg free base, once daily for 6 days; s.c.), and the effect of PFC stimulation was assessed on withdrawal days 2 and 10. In addition to single spike firing patterns, the ability of the stimulation to elicit stimulus bound (time-locked) burst events was also noted. In the majority of cases, the elicited responses could be broadly categorised into two types--ones characterised by an initial excitation (E responses) and ones characterised by excitation following an initial inhibition (IE responses). On withdrawal day 2, IE responses were affected such that, in those responses which contained time-locked bursts in their excitatory phases, the stimulus produced a time-locked burst on a greater percentage of trials. On withdrawal day 10, the principal change was that E responses were more likely to occur in amphetamine-treated animals than controls (0.25 mA; 57.1% vs. 41.2% of responses, respectively; 0.5 mA; 36.7% vs. 23.5% of responses, respectively). It is argued that an increase in the proportion of excitatory responses in drug animals indicates a potentiation of the excitatory drive to the DA neurons. Insofar as sensitisation in the longer term relies upon an enhancement of amphetamine-induced dopamine release in the forebrain, this may be one mechanism by which it is achieved.

Neurokinin agonists differentially affect A9 and A10 dopamine cells in the rat

The effect of selective neurokinin (NK) receptor agonists on the activity of A9 and A10 dopamine cells was assessed using extracellular recording. A higher proportion of A10 cells which were administered the NK1 receptor agonist GR73632 or the NK3 receptor agonist senktide showed an effect, whereas the NK2 receptor agonist GR64349 did not discriminate as clearly between the two cell groups. The most frequently encountered response in all cases was an increase in firing rate.