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Blindsight is the residual visuo-motor ability without subjective awareness observed after lesions of the primary visual cortex (V1). Various visual functions are retained, however, instrumental visual associative learning remains to be investigated. Here we examined the secondary reinforcing properties of visual cues presented to the hemianopic field of macaque monkeys with unilateral V1 lesions. Our aim was to test the potential role of visual pathways bypassing V1 in reinforcing visual instrumental learning. When learning the location of a hidden area in an oculomotor search task, conditioned visual cues presented to the lesion-affected hemifield operated as an effective secondary reinforcer. We noted that not only the hidden area location, but also the vector of the saccade entering the target area was reinforced. Importantly, when the visual reinforcement signal was presented in the lesion-affected field, the monkeys continued searching, as opposed to stopping when the cue was presented in the intact field. This suggests the monkeys were less confident that the target location had been discovered when the reinforcement cue was presented in the affected field. These results indicate that the visual signals mediated by the residual visual pathways after V1 lesions can access fundamental reinforcement mechanisms but with impaired visual, 盲視マカクサルは視覚意識が無くても自発的行動を学習できる. 京都大学プレスリリース. 2021-09-14., Using visual information to learn voluntary behavior while blind. 京都大学プレスリリース. 2021-09-14.

The dorsolateral striatum plays a critical role in the acquisition and expression of stimulus-response habits that are learned in experimental laboratories. Here, we use meta-analytic procedures to contrast the neural circuits activated by laboratory-acquired habits with those activated by stimulus-response behaviours acquired in everyday-life. We confirmed that newly learned habits rely more on the anterior putamen with activation extending into caudate and nucleus accumbens. Motor and associative components of everyday-life habits were identified. We found that motor-dominant stimulus-response associations developed outside the laboratory primarily engaged posterior dorsal putamen, supplementary motor area (SMA) and cerebellum. Importantly, associative components were also represented in the posterior putamen. Thus, common neural representations for both naturalistic and laboratory-based habits were found in the left posterior and right anterior putamen. These findings suggest a partial common striatal substrate for habitual actions that are performed predominantly by stimulus-response associations represented in the posterior striatum. The overlapping neural substrates for laboratory and everyday-life habits supports the use of both methods for the analysis of habitual behaviour.

Humans can simultaneously combine automatic/habitual and voluntary/goal-directed aspects of behavioral control. Habitual routines permit us to perform well practiced task-components with minimal or no voluntary attention. Evidence from animal and human investigations indicates that dopaminergic neurons in lateral substantia nigra, which innervate the sensorimotor striatum, are engaged during the acquisition and performance of automatized skills and habits. Typically, in Parkinson disease (PD), there is a differential loss of dopamine, which occurs earliest and most severely in the caudal sensorimotor striatum, a subdivision of the striatum implicated in habitual control. We suggest that frequent reliance on habitual performance may be a critical functional stressor, which, when combined with other more general risk factors, could explain the selective neurodegeneration of the nigrostriatal motor projection in PD.

Initial changes in Parkinson's disease (PD) are marked by loss of automatic movements and decline of some cognitive functions. Yet, the exact profile and extent of cognitive impairments in early stages of PD as well as their mechanisms related to automatic motor dysfunction remain unclear. Our objective was to examine the neuropsychological changes in early PD and their association to automatic and controlled modes of behavioural control. Significant relationships between early PD and cognitive dysfunction in set-shifting, abstraction ability/concept formation, processing speed, visuospatial/constructional abilities and verbal-visual memory was found. We also noted that tests with a strong effortful and controlled component were similarly affected as automatic tests by early PD, particularly those testing verbal memory, processing speed and visuospatial/constructional functions. Our findings indicate that initial stages of PD sets constraints over most of the cognitive domains normally assessed and are not easily explained in terms of either automatic or controlled mechanisms, as both appear similarly altered in early PD.

Escape is one of the most studied animal behaviors, and there is a rich normative theory that links threat properties to evasive actions and their timing. The behavioral principles of escape are evolutionarily conserved and rely on elementary computational steps such as classifying sensory stimuli and executing appropriate movements. These are common building blocks of general adaptive behaviors. Here we consider the computational challenges required for escape behaviors to be implemented, discuss possible algorithmic solutions, and review some of the underlying neural circuits and mechanisms. We outline shared neural principles that can be implemented by evolutionarily ancient neural systems to generate escape behavior, to which cortical encephalization has been added to allow for increased sophistication and flexibility in responding to threat.

Background\ud \ud Abnormal temporal discrimination in cervical dystonia is hypothesized to be attributable to disrupted processing in the superior colliculus. The fast, luminance‐based, retinotectal pathway, projects to the superior colliculus; chromatic stimuli responses, by the retino‐geniculo‐calcarine pathway, are up to 30 ms longer.\ud \ud \ud \ud Objectives\ud \ud We sought to interrogate visual processing and reaction times in patients with cervical dystonia compared with healthy controls. We hypothesized that cervical dystonia patients would have impaired reaction times to luminance based stimuli accessing the retino‐tectal pathway in comparison to healthy control participants.\ud \ud \ud \ud Methods\ud \ud In 20 cervical dystonia and 20 age‐matched control participants, we compared reaction times to two flashing visual stimuli: (1) a chromatic annulus and (2) a luminant, noncolored annulus. Participants pressed a joystick control when they perceived the annulus flashing.\ud \ud \ud \ud Results\ud \ud Reaction times in control participants were 20 ms significantly faster in the luminant condition than the chromatic (P = 0.017). Patients with cervical dystonia had no reaction time advantage in response to the luminant stimulus.\ud \ud \ud \ud Conclusion\ud \ud Cervical dystonia patients (compared to control participants) demonstrated no reduction in their reaction time to luminant stimuli, processed through the retinotectal pathway. This finding is consistent with superior colliculus dysfunction in cervical dystonia.

After classical conditioning dopamine (DA) neurons exhibit short latency responses to reward-predicting visual cues. At least two possible projections could induce such DA responses; the cortical and subcortical visual pathways. Our recent study has shown that after a lesion of the striate cortex (V1), the superior colliculus (SC), a critical node of the subcortical visual pathway, can mediate short latency cue responses in the DA neurons of macaque monkeys. An obvious question then is does the cortical pathway have a similar capacity? Using the monkeys with a unilateral V1 lesion that took part in the preceding study, we recorded DA activity while they were performing the same classical conditioning task. However, in this study conditioned visual stimuli were presented to the intact visual field, and the effects of ipsilateral SC inactivation were examined. We found that after the SC was inactivated by injections of muscimol both conditioned behavioral responding and reward-predicting, short latency (~100 ms) cue-elicited DA neuronal responses were unaffected These results indicate that the intact cortical visual pathway can also mediate short latency cue elicited responses in DA neurons in the absence of a normally functioning subcortical visual system.

Impaired neurovascular coupling has been suggested as an early pathogenic factor in Alzheimer’s disease (AD), which could serve as an early biomarker of cerebral pathology. We have established an anaesthetic regime to allow repeated measurements of neurovascular function over three months in the J20 mouse model of AD (J20-AD) and wild-type (WT) controls. Animals were 9–12 months old at the start of the experiment. Mice were chronically prepared with a cranial window through which 2-Dimensional optical imaging spectroscopy (2D-OIS) was used to generate functional maps of the cerebral blood volume and saturation changes evoked by whisker stimulation and vascular reactivity challenges. Unexpectedly, the hemodynamic responses were largely preserved in the J20-AD group. This result failed to confirm previous investigations using the J20-AD model. However, a final acute electrophysiology and 2D-OIS experiment was performed to measure both neural and hemodynamic responses concurrently. In this experiment, previously reported deficits in neurovascular coupling in the J20-AD model were observed. This suggests that J20-AD mice may be more susceptible to the physiologically stressing conditions of an acute experimental procedure compared to WT animals. These results therefore highlight the importance of experimental procedure when determining the characteristics of animal models of human disease.

Previous electrical stimulation and lesion experiments have suggested that the crossed descending output pathway from the deeper layers (SCd) of superior colliculus (SC) controls orienting responses, while the uncrossed pathway mediates defense-like behavior. Here we extended these investigations by using selective optogenetic activation of each pathway in mice with channelrhodopsin 2 expression by double viral vector techniques. Brief photo-stimulation of the crossed pathway evoked short latency contraversive orienting-like head turns, while extended stimulation induced contraversive circling responses. In contrast, stimulation of uncrossed pathway induced short-latency upward head movements followed by longer-latency defense-like behaviors including retreat and flight. The novel discovery was that the evoked defense-like responses varied depending on the environment, suggesting that uncrossed output can be influenced by top-down modification of the SC or its downstream. This further suggests that the SCd-defense system can be profoundly modulated by non-motor, affective and cognitive components, in addition to direct sensory inputs.

Inhibitory interneurons can evoke vasodilation and vasoconstriction, making them potential cellular drivers of neurovascular coupling. However, the specific regulatory roles played by particular interneuron subpopulations remain unclear. Our purpose was therefore to adopt a cell-specific optogenetic approach to investigate how somatostatin (SST) and neuronal nitric oxide synthase (nNOS)-expressing interneurons might influence the neurovascular relationship. In mice, specific activation of SST- or nNOS-interneurons was sufficient to evoke hemodynamic changes. In the case of nNOS-interneurons, robust hemodynamic changes occurred with minimal changes in neural activity, suggesting that the ability of blood oxygen level dependent functional magnetic resonance imaging (BOLD fMRI) to reliably reflect changes in neuronal activity may be dependent on type of neuron recruited. Conversely, activation of SST-interneurons produced robust changes in evoked neural activity with shallow cortical excitation and pronounced deep layer cortical inhibition. Prolonged activation of SST-interneurons often resulted in an increase in blood volume in the centrally activated area with an accompanying decrease in blood volume in the surrounding brain regions, analogous to the negative BOLD signal. These results demonstrate the role of specific populations of cortical interneurons in the active control of neurovascular function.

Electrical stimulation and lesion experiments in 1980’s suggested that the crossed descending pathway from the deeper layers of superior colliculus (SCd) controls orienting responses, while the uncrossed pathway mediates defense-like behavior. To overcome the limitation of these classical studies and explicitly dissect the structure and function of these two pathways, we performed selective optogenetic activation of each pathway in male mice with channelrhodopsin 2 (ChR2) expression by Cre driver using double viral vector techniques. Brief photostimulation of the crossed pathway evoked short latency contraversive orienting-like head turns, while extended stimulation induced body turn responses. In contrast, stimulation of the uncrossed pathway induced short-latency upward head movements followed by longer-latency defense-like behaviors including retreat and flight. The novel discovery was that while the evoked orienting responses were stereotyped, the defense-like responses varied considerably depending on the environment, suggesting that uncrossed output can be influenced by top-down modification of the SC or its target areas. This further suggests that the connection of the SCd-defense system with non-motor, affective and cognitive structures. Tracing the whole axonal trajectories of these two pathways revealed existence of both ascending and descending branches targeting different areas in the thalamus, midbrain, pons, medulla, and/or spinal cord, including projections which could not be detected in the classical studies; the crossed pathway has some ipsilaterally descending collaterals and the uncrossed pathway has some contralaterally descending collaterals. Some of the connections might explain the context-dependent modulation of the defense-like responses. Thus, the classical views on the tectal output systems are updated.

Neurovascular coupling is the process by which neural activity causes localised changes in cerebral blood flow. Impaired neurovascular coupling has been suggested as an early pathogenic factor in Alzheimer’s disease (AD), and if so, could serve as an early biomarker of cerebral pathology. We have established an anaesthetic regime in which evoked hemodynamic responses are comparable to those in awake mice. This protocol was adapted to allow repeated measurements of neurovascular function over three months in the hAPP-J20 mouse model of AD (J20-AD) and wild-type (WT) controls. Animals were 9-12 months old at the start of the experiment, which is when deficits due to the disease condition would be expected. Mice were chronically prepared with a cranial window through which optical imaging spectroscopy (OIS) was used to generate functional maps of the cerebral blood volume and saturation changes evoked by whisker stimulation and vascular reactivity challenges. Unexpectedly, the hemodynamic responses were largely preserved in the J20-AD group. This result failed to confirm previous investigations using the J20-AD model. However, a final acute electrophysiology and OIS experiment was performed to measure both neural and hemodynamic responses concurrently. In this experiment, previously reported deficits in neurovascular coupling in the J20-AD model were observed. This suggests that J20-AD mice may be more susceptible to the physiologically stressing conditions of an acute experimental procedure compared to WT animals. These results therefore highlight the importance of experimental procedure when determining the characteristics of animal models of human disease.Significance StatementUsing a chronic anaesthetised preparation, we measured hemodynamic responses evoked by sensory stimulation and respiratory gases in the J20-AD mouse model of Alzheimer’s Disease over a period of 3 months. We showed that neurovascular responses were preserved compared to age matched wildtype controls. These results failed to confirm previous investigations reporting a marked reduction of neurovascular coupling in the J20-AD mouse model. However, when our procedure involved acute surgical procedures, previously reported neurovascular deficits were observed. The effects of acute electrode implantation were caused by disturbances to baseline physiology rather than a consequence of the disease condition. These results highlight the importance of experimental procedure when determining the characteristics of animal models of human disease.

Anesthetized rodent models are ubiquitous in pre-clinical neuroimaging studies. However, because the associated cerebral morphology and experimental methodology results in a profound negative brain-core temperature differential, cerebral temperature changes during functional activation are likely to be principally driven by local inflow of fresh, core-temperature, blood. This presents a confound to the interpretation of blood-oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) data acquired from such models, since this signal is also critically temperature-dependent. Nevertheless, previous investigation on the subject is surprisingly sparse. Here, we address this issue through use of a novel multi-modal methodology in the urethane anesthetized rat. We reveal that sensory stimulation, hypercapnia and recurrent acute seizures induce significant increases in cortical temperature that are preferentially correlated to changes in total hemoglobin concentration, relative to cerebral blood flow and oxidative metabolism. Furthermore, using a phantom-based evaluation of the effect of such temperature changes on the BOLD fMRI signal, we demonstrate a robust inverse relationship between the two. These findings indicate that temperature increases, due to functional hyperemia, should be accounted for to ensure accurate interpretation of BOLD fMRI signals in pre-clinical neuroimaging studies.

Deep brain stimulation applied at high frequency (HFS) to the subthalamic nucleus (STN) is used to ameliorate the symptoms of Parkinson's disease. The mechanism by which this is achieved remains controversial. In particular, it is uncertain whether HFS has a suppressive or excitatory action locally within the STN. Brief exposure of rats to ether anesthesia evokes pathological burst firing and associated expression of the immediate early gene c-Fos in STN neurons. We used this ether model of STN activation to test the effect of a range of HFS parameters on c-Fos expression evoked by the anesthetic. The elevated baseline of c-Fos expression afforded the possibility of detecting further excitatory, or suppressive effects of STN HFS. Four HFS protocols were examined; 130, 200 and 260 Hz with 60 µs, and 130 Hz with 90 µs pulse width (HFS intensity:150-300 µA). All HFS protocols were applied for 20 min while the animals were exposed to ether. Ether-evoked expression of c-Fos immunoreactivity was suppressed by HFS at 200 and 260 Hz with a pulse width of 60 µs, and by 130 Hz when the pulse width was increased to 90 µs. HFS at 130 Hz with the 60 µs pulse width had no significant effect and HFS alone caused negligible c-Fos expression in the STN. These findings suggest that HFS of the STN causes significant suppression of evoked neuronal activity. It remains to be determined whether this locally suppressive property of HFS is associated with the efficacy of STN deep brain stimulation to relieve the symptoms of Parkinson's disease.

Whether functional hyperemia during epileptic activity is adequate to meet the heightened metabolic demand of such events is controversial. Whereas some studies have demonstrated hyperoxia during ictal onsets, other work has reported transient hypoxic episodes that are spatially dependent on local surface microvasculature. Crucially, how laminar differences in ictal evolution can affect subsequent cerebrovascular responses has not been thus far investigated, and is likely significant in view of possible laminar-dependent neurovascular mechanisms and angioarchitecture. We addressed this open question using a novel multi-modal methodology enabling concurrent measurement of cortical tissue oxygenation, blood flow and hemoglobin concentration, alongside laminar recordings of neural activity, in a urethane anesthetized rat model of recurrent seizures induced by 4-aminopyridine. We reveal there to be a close relationship between seizure epicenter depth, translaminar local field potential (LFP) synchrony and tissue oxygenation during the early stages of recurrent seizures, whereby deep layer seizures are associated with decreased cross laminar synchrony and prolonged periods of hypoxia, and middle layer seizures are accompanied by increased cross-laminar synchrony and hyperoxia. Through comparison with functional activation by somatosensory stimulation and graded hypercapnia, we show that these seizure-related cerebrovascular responses occur in the presence of conserved neural-hemodynamic and blood flow-volume coupling. Our data provide new insights into the laminar dependency of seizure-related neurovascular responses, which may reconcile inconsistent observations of seizure-related hypoxia in the literature, and highlight a potential layer-dependent vulnerability that may contribute to the harmful effects of clinical recurrent seizures. The relevance of our findings to perfusion-related functional neuroimaging techniques in epilepsy are also discussed., Highlights • Laminar LFP synchrony during seizures influences tissue oxygenation responses. • Seizures with deep epicenters were associated with reduced cross-laminar synchrony. • Seizures with deep epicenters were associated with tissue hypoxia. • Effects observed despite increases in CBF and conserved neural-hemodynamic coupling. • Suggests possible laminar susceptibility to tissue hypoxia during ictal events.

Plasticity at synapses between the cortex and striatum is considered critical for learning novel actions. However, investigations of spike-timing-dependent plasticity (STDP) at these synapses have been performed largely in brain slice preparations, without consideration of physiological reinforcement signals. This has led to conflicting findings, and hampered the ability to relate neural plasticity to behavior. Using intracellular striatal recordings in intact rats, we show here that pairing presynaptic and postsynaptic activity induces robust Hebbian bidirectional plasticity, dependent on dopamine and adenosine signaling. Such plasticity, however, requires the arrival of a reward-conditioned sensory reinforcement signal within 2 s of the STDP pairing, thus revealing a timing-dependent eligibility trace on which reinforcement operates. These observations are validated with both computational modeling and behavioral testing. Our results indicate that Hebbian corticostriatal plasticity can be induced by classical reinforcement learning mechanisms, and might be central to the acquisition of novel actions., Spike timing dependent plasticity (STDP) has been studied extensively in slices but whether such pairings can induce plasticity in vivo is not known. Here the authors report an experimental paradigm that achieves bidirectional corticostriatal STDP in vivo through modulation by behaviourally relevant reinforcement signals, mediated by dopamine and adenosine signaling.

Responses of midbrain dopamine (DA) neurons reflecting expected reward from sensory cues are critical for reward-based associative learning. However, critical pathways by which reward-related visual information is relayed to DA neurons remain unclear. To address this question, we investigated Pavlovian conditioning in macaque monkeys with unilateral primary visual cortex (V1) lesions (an animal model of ‘blindsight’). Anticipatory licking responses to obtain juice drops were elicited in response to visual conditioned stimuli (CS) in the affected visual field. Subsequent pharmacological inactivation of the superior colliculus (SC) suppressed the anticipatory licking. Concurrent single unit recordings indicated that DA responses reflecting the reward expectation could be recorded in the absence of V1, and that these responses were also suppressed by SC inactivation. These results indicate that the subcortical visual circuit can relay reward-predicting visual information to DA neurons and integrity of the SC is necessary for visually-elicited classically conditioned responses after V1 lesion. DOI: http://dx.doi.org/10.7554/eLife.24459.001, eLife digest To survive and thrive, animals must learn to approach cues in their environment that are likely to lead to a desirable outcome and avoid those that might lead them to harm. A group of brain regions known as the midbrain dopamine system helps many animals to achieve this. Dopamine is the brain’s reward signal. Cues that predict rewards, such as the sight or smell of food, activate midbrain dopamine neurons. However, the details of this process remained unclear. Takakuwa et al. have now examined how visual information that signals reward reaches the midbrain dopamine neurons. The anatomy of the visual system suggests two main possibilities. Information may travel directly from the eyes to an area of the midbrain called the superior colliculus, and then onto the dopamine neurons. Alternatively, information may travel to the midbrain indirectly via a pathway that includes additional processing in the brain’s outer layer, the visual cortex. To distinguish between these routes, Takakuwa et al. studied monkeys in which the indirect pathway via the visual cortex had been damaged. Some people with damage to this pathway have a disorder called blindsight. They are able to detect the movement or location of stimuli, but they cannot consciously see those stimuli. The monkeys with damage to visual cortex were able to learn that an image on a screen predicted the delivery of fruit juice. After repeated trials, the monkeys began to lick the spout dispensing the juice whenever the image appeared, even if no juice was delivered. The monkeys’ midbrain dopamine neurons also sent more signals in response to the images, and showed greater activity when the images predicted large rewards than small ones. Takakuwa et al. next inactivated the superior colliculus with a drug and showed that this prevented both the licking behavior and the increased signaling. Together the findings show that visual information about potential rewards can reach midbrain dopamine neurons via a direct route through the superior colliculus, without needing to pass via the visual cortex. The next step is to determine how and when the visual cortex may get involved in this process to help animals maximize rewards. DOI: http://dx.doi.org/10.7554/eLife.24459.002

Repeated electrical stimulation of dopamine (dopamine) fibers can cause variable effects on further dopamine release; sometimes there are short-term decreases while in other cases short-term increases have been reported. Previous studies have failed to discover what factors determine in which way dopamine neurons will respond to repeated stimulation. The aim of the present study was therefore to investigate what determines the direction and magnitude of this particular form of short-term plasticity. Fixed potential amperometry was used to measure dopamine release in the nucleus accumbens in response to two trains of electrical pulses administered to the ventral tegmental area of anesthetized mice. When the pulse trains were of equal magnitude we found that low magnitude stimulation was associated with short-term suppression and high magnitude stimulation with short-term facilitation of dopamine release. Secondly, we found that the magnitude of the second pulse train was critical for determining the sign of the plasticity (suppression or facilitation), while the magnitude of the first pulse train determined the extent to which the response to the second train was suppressed or facilitated. This form of bidirectional plasticity might provide a mechanism to enhance signal-to-noise ratio of dopamine neurotransmission.

Dopaminergic (DA) neurons respond to stimuli in a wide range of modalities, although the origin of the afferent sensory signals has only recently begun to emerge. In the case of vision, an important source of short-latency sensory information seems to be the midbrain superior colliculus (SC). However, longer-latency responses have been identified that are less compatible with the primitive perceptual capacities of the colliculus. Rather, they seem more in keeping with the processing capabilities of the cortex. Given that there are robust projections from the cortex to the SC, we examined whether cortical information could reach DA neurons via a relay in the colliculus. The somatosensory barrel cortex was stimulated electrically in the anesthetized rat with either single pulses or pulse trains. Although single pulses produced small phasic activations in the colliculus, they did not elicit responses in the majority of DA neurons. However, after disinhibitory intracollicular injections of the GABAA antagonist bicuculline, collicular responses were substantially enhanced and previously unresponsive DA neurons now exhibited phasic excitations or inhibitions. Pulse trains applied to the cortex led to phasic changes (excitations to inhibitions) in the activity of DA neurons at baseline. These were blocked or attenuated by intracollicular administration of the GABAA agonist muscimol. Taken together, the results indicate that the cortex can communicate with DA neurons via a relay in the SC. As a consequence, DA neuronal activity reflecting the unexpected occurrence of salient events and that signaling more complex stimulus properties may have a common origin.

The literature on motor learning in patients with Parkinson’s disease and the potential remedial effects of medication with L-dopa has yet to converge on an agreed message. Rather, many carefully controlled studies have produced a range of results beset with inconsistencies. Although, given the complexity of the neural networks implicated in generating adaptive movement, perhaps we should not be so surprised. Some of the important factors that interact to influence the variable outcomes of relevant experiments have already been identified. First, the concept of what constitutes, and the terms used to describe adaptive motor control can vary in different literatures. An important and clarifying distinction is between the acquisition of a motor skill (improvements in speed and accuracy), and motor adaptation (shifts in performance favoring speed or accuracy, or some form of sensorimotor recalibration). However, misunderstandings have arisen by researchers in different disciplines using different words for the same thing, and the same words for different things. For example, the concepts of conscious, voluntary, explicit, controlled, goal-directed, and model-based motor learning overlap, but may not be identical. Similarly, unconscious, involuntary, implicit, automatic, habitual and model-free motor learning may represent similar phenomenon at different levels of description. But at our present stage of understanding, it may be unwise to consider them as synonymous. It is possible, therefore, that some of the seemingly paradoxical findings in the motor learning literature arise through a lack of an agreed nomenclature and taxonomy. Secondly, many tasks of varying complexity have been used to investigate different aspects of motor learning in patients with Parkinson’s disease. However, for understandably practical reasons (issues associated with testing elderly patients), most studies have confined themselves to investigations of the rapid, early stages of learning. The levels of practice required for automatized, habitual control to become fully established have usually been avoided. Consequently, the current motor skill literature with patients is likely to be biased towards their refinement of goaldirected movements. Moreover, some more complex tasks could require variable mixtures of goal-directed and previously acquired habitual control. This is important because regionally segregated functional territories of the basal ganglia are differentially engaged during goal-directed and habitual control of behavior. Thirdly, Parkinson’s disease is a progressive disorder, which in itself has important implications for investigations of motor learning. Because many of the tests measure speed of responding, the difficulties patients experience in initiating movement and bradykinesia at different stages of the disease could account for some of the variable results. A further source of variability may be the progressive and sequential loss of dopamine from the regionally segregated functional territories of the basal ganglia. Typically, dopaminergic innervation is lost first from the sensorimotor territories of the caudal putamen, which over time, extends forward and ventrally to encompass the associative and limbic territories. Insofar as habits are associated with the sensorimotor basal ganglia, and goal-directed actions with the associative territories, patients tested at different stages of Parkinson’s disease will vary in their ability to acquire, perform and refine goal-directed actions and habits. Finally, when one part of the brain fails, other parts frequently adapt. Tests conducted at different stages of the disease may therefore face a variable interplay between degenerative and adaptive mechanisms. Fourthly, a critically important factor is whether patients are tested ON or OFF dopamine-restoring medication, usually L-dopa and/or direct acting dopaminergic agonists. Typically, patients receive sufficient medication to relieve their motor systems. In practice, this means a level of medication sufficient to restore dopaminergic transmission in the dopamine deprived sensorimotor basal ganglia. However, in patients where dopaminergic transmission in the associative and limbic territories is preserved, their medication is likely to produce supranormal levels of dopaminergic transmission. This effect may be -----------------------------------------------------------*Correspondence to: Peter Redgrave Dept. Psychology, University of Sheffield, Sheffield, S10 2TN, U.K.; P.Redgrave@sheffield.ac.uk

Midbrain dopamine neurons play critical roles in reward- and aversion-driven associative learning. However, it is not clear whether they do this by a common mechanism or by separate mechanisms that can be dissociated. In the present study we addressed this question by testing whether a partial lesion of the dopamine neurons of the rat SNc has comparable effects on conditioned place preference (CPP) learning and conditioned place aversion (CPA) learning. Partial lesions of dopamine neurons in the rat substantia nigra pars compacta (SNc) induced by bilateral intranigral infusion of 6-hydroxydopamine (6-OHDA, 3μg/side) or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 200μg/side) impaired learning of conditioned place aversion (CPA) without affecting conditioned place preference (CPP) learning. Control experiments demonstrated that these lesions did not impair motor performance and did not alter the hedonic value of the sucrose and quinine. The number of dopamine neurons in the caudal part of the SNc positively correlated with the CPP scores of the 6-OHDA rats and negatively correlated with CPA scores of the SHAM rats. In addition, the CPA scores of the 6-OHDA rats positively correlated with the tissue content of striatal dopamine. Insomuch as reward-driven learning depends on an increase in dopamine release by nigral neurons, these findings show that this mechanism is functional even in rats with a partial lesion of the SNc. On the other hand, if aversion-driven learning depends on a reduction of extracellular dopamine in the striatum, the present study suggests that this mechanism is no longer functional after the partial SNc lesion.

Parkinson’s disease (PD) is a neurodegenerative disorder that markedly affects voluntary action. While regular dopamine treatment can help restore motor function, dopamine also influences cognitive portions of the action system. Previous studies have demonstrated that dopamine medication boosts action-effect associations, which are crucial for the discovery of new voluntary actions. In the present study, we investigated whether neural processes involved in the discovery of new actions are altered in PD participants on regular dopamine treatment, compared to healthy age-match controls. We recorded brain electroencephalography (EEG) activity while PD patients and age-matched controls performed action discovery and action control tasks. We found that the novelty P3, a component normally present when there is uncertainty about the occurrence of the sensory effect, was enhanced in PD patients. However, action discovery was maintained in PD patients, and the novelty P3 demonstrated normal learning-related reductions. Crucially, we found that in PD patients the causal association between an action and its resulting sensory outcome did not modulate the amplitude of the feedback correct-related positivity (fCRP), an EEG component sensitive to the association between an action and its resulting effect. Collectively, these preliminary results suggest that the formation of long-term action-outcome representations may be maintained in PD patients on regular dopamine treatment, but the initial experience of action-effect association may be affected.

The present chapter begins by reviewing some of the influential ideas on basal ganglia involvement in action selection and reinforcement learning. Within this context, we assess the specific contribution of the phasic response of dopamine (DA) neurons to the fundamental processes of reinforcement learning. Since the turn of the century, the dominant hypothesis has been that sensory-evoked DA responses signal reward prediction errors—events that are better or worse than expected. The reinforcing effects of these signals are to ensure that future reward acquisition is maximized. One of the few arguments against this view was that phasic DA signals are unlikely to signal a generally useful reward prediction error because their short latency ( before the identity of the event has been established? However, recent evidence that cortical visual processing can also elicit phasic DA responses means the argument that short latency of phasic DA signaling is too short to signal reward prediction errors is no long applicable. This important new perspective is incorporated into our previously articulated hypothesis that phasic DA signaling would be useful for the determination of agency and the discovery of novel actions.

Although the existence of prominent connections between the intralaminar thalamic nuclei and the basal ganglia has long been established, the limited knowledge of the functional relevance of this network has considerably hampered progress in our understanding of the neural mechanisms by which the thalamostriatal system integrates and regulates the basal ganglia circuitry. In this brief commentary, we will address this gap of knowledge through a discussion of the key points of a symposium entitled “Thalamic Contributions to Basal Ganglia-Related Behavioral Switching and Reinforcement” that will be presented at the 2011 Society for Neuroscience meeting. Recent anatomical and physiological data that support the role of the thalamostriatal system in action selection, attentional shifting, and reinforcement will be discussed. We will also address the possibility that degeneration of the thalamostriatal system could underlie some of the deficits in redirection of attention in response to salient stimuli seen in Parkinson's disease.

Modern neuroimaging techniques rely on neurovascular coupling to show regions of increased brain activation. However, little is known of the neurovascular coupling relationships that exist for inhibitory signals. To address this issue directly we developed a preparation to investigate the signal sources of one of these proposed inhibitory neurovascular signals, the negative blood oxygen level-dependent (BOLD) response (NBR), in rat somatosensory cortex. We found a reliable NBR measured in rat somatosensory cortex in response to unilateral electrical whisker stimulation, which was located in deeper cortical layers relative to the positive BOLD response. Separate optical measurements (two-dimensional optical imaging spectroscopy and laser Doppler flowmetry) revealed that the NBR was a result of decreased blood volume and flow and increased levels of deoxyhemoglobin. Neural activity in the NBR region, measured by multichannel electrodes, varied considerably as a function of cortical depth. There was a decrease in neuronal activity in deep cortical laminae. After cessation of whisker stimulation there was a large increase in neural activity above baseline. Both the decrease in neuronal activity and increase above baseline after stimulation cessation correlated well with the simultaneous measurement of blood flow suggesting that the NBR is related to decreases in neural activity in deep cortical layers. Interestingly, the magnitude of the neural decrease was largest in regions showing stimulus-evoked positive BOLD responses. Since a similar type of neural suppression in surround regions was associated with a negative BOLD signal, the increased levels of suppression in positive BOLD regions could importantly moderate the size of the observed BOLD response.

Comparison of 3T blood oxygenation level dependent (BOLD) and cerebral blood volume (CBV) activation maps to histological sections enables the spatial discrimination of functional magnetic resonance imaging (fMRI) signal changes into different vascular compartments. We use a standard gradient echo-echo planar imaging technique to measure BOLD signal changes in the somatosensory cortex in response to whisker stimulation. Corresponding changes in CBV were estimated following the infusion of a super-paramagnetic contrast agent. We imaged in a tangential imaging plane that covered the cortical surface. Images were associated with post mortem histological sections showing both the surface vasculature and cytochrome oxidase stained whisker barrel cortex. We found a significant BOLD signal change in the large draining veins which occurred in the absence of a corresponding CBV change. Results suggest that in the venous drainage system, ~3mm distant from the area of activity, there is a robust change in blood oxygen saturation with little or no volume change. CBV changes are localised over the somatosensory barrel cortex and overlying arterial supply, supporting the theory that CBV changes are greater in the arterial than in the venous vasculature. This work investigating BOLD signal and underlying hemodynamics provides more information on the vascular origins of these important neuroimaging signals.

The striatum is a site of integration of neural pathways involved in reinforcement learning. Traditionally, inputs from cerebral cortex are thought to be reinforced by dopaminergic afferents signaling the occurrence of biologically salient sensory events. Here, we detail an alternative route for short-latency sensory-evoked input to the striatum requiring neither dopamine nor the cortex. Using intracellular recording techniques, we measured subthreshold inputs to spiny projection neurons (SPNs) in urethane-anesthetized rats. Contralateral whole-field light flashes evoked weak membrane potential responses in approximately two-thirds of neurons. However, after local disinhibitory injections of the GABAAantagonist bicuculline into the deep layers of the superior colliculus (SC), but not the overlying visual cortex, strong, light-evoked, depolarizations to the up state emerged at short latency (115 ± 14 ms) in all neurons tested. Dopamine depletion using α-methyl-para-tyrosine had no detectable effect on striatal visual responses during SC disinhibition. In contrast, local inhibitory injections of GABA agonists, muscimol and baclofen, into the parafascicular nucleus of the thalamus blocked the early, visual-evoked up-state transitions in SPNs. Comparable muscimol-induced inhibition of the visual cortex failed to suppress the visual responsiveness of SPNs induced by SC disinhibition. Together, these results suggest that short-latency, preattentive visual input can reach the striatum not only via the tecto-nigro-striatal route but also through tecto-thalamo-striatal projections. Thus, after the onset of a biologically significant visual event, closely timed short-latency thalamostriatal (glutamate) and nigrostriatal (dopamine) inputs are likely to converge on striatal SPNs, providing depolarizing and neuromodulator signals necessary for synaptic plasticity mechanisms.

In addition to rods and cones of the outer retina, a third class of photoreceptive cell has recently been described in the inner retina of mammals. These intrinsically photosensitive retinal ganglion cells (ipRGCs) have been shown to relay luminance information to the mammalian brain. In addition to their intrinsic photosensitivity, the function of ipRGCs may also be modulated by signals from within the retina itself. Such signals may emanate from classical photoreceptors in the outer retina or from the circadian activity of adjacent inner retinal neurones. Prime candidates for the latter are the retinal dopamine neurones which ramify at the border of the inner plexiform and inner nuclear layers. In order to investigate the nature of any interaction between dopamine and ipRGC populations in normal retina and to assess the impact of outer retinal degeneration on this interrelationship, we examined the retinae of normal and RCS dystrophic rats. We report a direct interaction between the dendrites of ipRGCs and dopaminergic neurones which is conserved across species. Triple immunolabelling using synaptic markers provides evidence for the unidirectionality of information transfer between the two cell types, with processes of ipRGCs being directly adjacent to sites of dopamine release. This fundamental architectural feature of the mammalian retina appears resistant to degeneration of classical photoreceptors and may provide the anatomical substrate by which dopamine cells influence the physiology of central circadian targets in the brain.