Midbrain Pathways Research Articles

Sound elicits stereotyped facial movements that provide a sensitive index of hearing abilities in mice

Sound elicits rapid movements of muscles in the face, ears, and eyes that protect the body from injury and trigger brain-wide internal state changes. Here, we performed quantitative facial videography from mice resting atop a piezoelectric force plate and observed that broadband sounds elicited rapid and stereotyped facial twitches. Facial motion energy (FME) adjacent to the whisker array was 30 dB more sensitive than the acoustic startle reflex and offered greater inter-trial and inter-animal reliability than sound-evoked pupil dilations or movement of other facial and body regions. FME tracked the low-frequency envelope of broadband sounds, providing a means to study behavioral discrimination of complex auditory stimuli, such as speech phonemes in noise. Approximately 25% of layer 5-6 units in the auditory cortex (ACtx) exhibited firing rate changes during facial movements. However, FME facilitation during ACtx photoinhibition indicated that sound-evoked facial movements were mediated by a midbrain pathway and modulated by descending corticofugal input. FME and auditory brainstem response (ABR) thresholds were closely aligned after noise-induced sensorineural hearing loss, yet FME growth slopes were disproportionately steep at spared frequencies, reflecting a central plasticity that matched commensurate changes in ABR wave 4. Sound-evoked facial movements were also hypersensitive in Ptchd1 knockout mice, highlighting the use of FME for identifying sensory hyper-reactivity phenotypes after adult-onset hyperacusis and inherited deficiencies in autism risk genes. These findings present a sensitive and integrative measure of hearing while also highlighting that even low-intensity broadband sounds can elicit a complex mixture of auditory, motor, and reafferent somatosensory neural activity.

Hypothalamic interaction with reward-related regions during subjective evaluation of foods

The reward system implemented in the midbrain, ventral striatum, orbitofrontal cortex, and ventromedial prefrontal cortex evaluates and compares various types of rewards given to the organisms. It has been suggested that autonomic factors influence reward-related processing via the hypothalamus, but how the hypothalamus modulates the reward system remains elusive. In this functional magnetic resonance imaging study, the hypothalamus was parcellated into individual hypothalamic nuclei performing different autonomic functions using boundary mapping parcellation analyses. The effective interaction during subjective evaluation of foods in a reward task was then investigated between the human hypothalamic nuclei and the reward-related regions. We found significant brain activity decrease in the paraventricular nucleus (PVH) and lateral nucleus in the hypothalamus in food evaluation compared with monetary evaluation. A psychophysiological interaction analysis revealed dual interactions between the PVH and (1) midbrain region and (2) ventromedial prefrontal cortex, with the former correlated with the stronger tendency of participants toward food-seeking. A dynamic causal modeling analysis further revealed unidirectional interactions from the PVH to the midbrain and ventromedial prefrontal cortex. These results suggest that the PVH in the human hypothalamus interacts with the reward-related regions in the cerebral cortex via multiple pathways (i.e., the midbrain pathway and ventromedial prefrontal pathway) to evaluate rewards for subsequent decision-making.

Limbic and Executive Meso- and Nigrostriatal Tracts Predict Impulsivity Differences in Attention-Deficit/Hyperactivity Disorder

BackgroundImpulsivity is a defining characteristic of attention-deficit/hyperactivity disorder (ADHD), which has been associated with substance use disorders, higher accident rates, and lower educational and occupational outcomes. The meso- and nigrostriatal pathways of the dopamine system are hypothesized to be functionally heterogeneous, supporting diverse cognitive functions and impairments, including those associated with ADHD. We tested whether human midbrain pathways (where dopaminergic cell bodies originate) between the substantia nigra (SN) and ventral tegmental area (VTA) and the striatum differed between participants with ADHD and typically developing adolescent and young adult participants. We also assessed whether pathway connectivity predicted impulsivity regardless of diagnosis. MethodsDiffusion tensor imaging data were used to predict impulsivity (parent and self-report ratings, task-based behavioral measures) from participants with ADHD and typically developing adolescent and young adult participants (n = 155; 86 male, 69 female). Using probabilistic tractography, we mapped these pathways and divided the tracts into limbic, executive, and sensorimotor based on frontostriatal connectivity. ADHD and typically developing participants differed on all behavioral measures of impulsivity. We used correlation and machine learning analyses to test for a relationship between tract probabilities and impulsivity regardless of diagnosis. ResultsParticipants with ADHD had stronger structural connectivity between SN/VTA regions and the limbic striatum, weaker connectivity with the executive striatum, and no significant differences in sensorimotor tracts. Increased tract integrity between the limbic striatal and SN/VTA regions predicted greater impulsivity, while increased integrity between executive striatal and SN/VTA regions predicted reduced impulsivity. ConclusionsThese findings support the theory that functional diversity in the dopamine system is an important consideration for understanding dysfunction in ADHD.

Mapping the living mouse brain neural architecture: strain-specific patterns of brain structural and functional connectivity.

Mapping brain structural and functional connectivity (FC) became an essential approach in neuroscience as network properties can underlie behavioral phenotypes. In mouse models, revealing strain-related patterns of brain wiring is crucial, since these animals are used to answer questions related to neurological or neuropsychiatric disorders. C57BL/6 and BALB/cJ strains are two of the primary "genetic backgrounds" for modeling brain disease and testing therapeutic approaches. However, extensive literature describes basal differences in the behavioral, neuroanatomical and neurochemical profiles of the two strains, which raises questions on whether the observed effects are pathology specific or depend on the genetic background of each strain. Here, we performed a systematic comparative exploration of brain structure and function of C57BL/6 and BALB/cJ mice using Magnetic Resonance Imaging (MRI). We combined deformation-based morphometry (DBM), diffusion MRI and high-resolution fiber mapping (hrFM) along with resting-state functional MRI (rs-fMRI) and demonstrated brain-wide differences in the morphology and "connectome" features of the two strains. Essential inter-strain differences were depicted regarding the size and the fiber density (FD) within frontal cortices, along cortico-striatal, thalamic and midbrain pathways as well as genu and splenium of corpus callosum. Structural dissimilarities were accompanied by specific FC patterns, emphasizing strain differences in frontal and basal forebrain functional networks as well as hubness characteristics. Rs-fMRI data further indicated differences of reward-aversion circuitry and default mode network (DMN) patterns. The inter-hemispherical FC showed flexibility and strain-specific adjustment of their patterns in agreement with the structural characteristics.

SUN-LB45 Identifying a Role for Lactogenic Hormones in Maternal Motivation

The onset of appropriate maternal behaviour is essential for the survival of dependent offspring in mammals. Lactogenic hormones, including prolactin and placental lactogen, play an important role in the regulation of this behaviour, mediated through prolactin receptor expression in the medial preoptic area (MPOA) of the hypothalamus1. However, it is unclear how lactogenic action in this region induces the display of maternal behaviour. It has been shown that activation of neuronal projections from the MPOA to the ventral tegmental area (VTA) is necessary for maternal behaviour2, with reward circuitry activated in order to motivate a mother to invest in time- and resource-costly care for her young. We aimed to investigate whether lactogenic hormones play a role in the activation of reward circuitry for maternal behaviour. First, we characterised specific aspects of motivation and reward behaviour in wildtype female C57BL/6 mice of different reproductive states, using three behavioural testing paradigms. We showed that virgin and pregnant mice develop a preference for contexts associated with the presence of foster pups in a conditioned place preference test (p<0.01, n=9 per group), an aspect of reward behaviour that was not observed in lactating females (p=0.14, n=8). However, in a novel T maze and when a climbable barrier was placed in the home cage, virgin and pregnant mice showed low motivation for pup retrieval compared to lactating mice (p<0.05, n≤6 per group). These data demonstrate that reproductive state differentially affects passive reward learning and active motivation for maternal care in wildtype mice. Moreover, we can differentiate between maternal and non-maternal states of pup-related reward behaviour with the use of the T maze and barrier climbing paradigms. Next, we tested mice with a conditional deletion of prolactin receptors in Gamma-Aminobutyric Acid (GABA) neurons (Prlr flox/VGat Cre) in the T maze during lactation. Knockout mice showed incomplete retrieval behaviour, and latencies for pup retrieval were significantly longer than in controls (p<0.01, n≤6 per group). The behavioural impairments observed in Prlr flox/VGat Cre knockout mice in the T maze imply that the action of lactogenic hormones on GABA neurons is required for full maternal motivation.1.Brown RSE, et al. Prolactin action in the medial preoptic area is necessary for postpartum maternal nursing behavior. Proc Natl Acad Sci U S A114, 10779-10784 (2017). 2.Fang YY, Yamaguchi T, Song SC, Tritsch NX, Lin D. A Hypothalamic Midbrain Pathway Essential for Driving Maternal Behaviors. Neuron98, 192-207 e110 (2018).

A Hypothalamic Midbrain Pathway Essential for Driving Maternal Behaviors

Maternal behaviors are essential for the survival of the young. Previous studies implicated the medial preoptic area (MPOA) as an important region for maternal behaviors, but details of the maternal circuit remain incompletely understood. Here we identify estrogen receptor alpha (Esr1)-expressing cells inthe MPOA as key mediators of pup approach andretrieval. Reversible inactivation of MPOAEsr1+ cells impairs those behaviors, whereas optogenetic activation induces immediate pup retrieval. Invivo recordings demonstrate preferential activation of MPOAEsr1+ cells during maternal behaviors and changes in MPOA cell responses across reproductive states. Furthermore, channelrhodopsin-assisted circuit mapping reveals a strong inhibitory projection from MPOAEsr1+ cells to ventral tegmental area (VTA) non-dopaminergic cells. Pathway-specific manipulations reveal that this projection is essential for driving pup approach and retrieval and that VTA dopaminergic cells are reliably activated during those behaviors. Altogether, this study provides new insight into the neural circuit that generates maternal behaviors.

Accumbal dopamine D1 receptor neurons control wakefulness by midbrain and lateral hypothalamus pathways

Accumbal dopamine D1 receptor neurons control wakefulness by midbrain and lateral hypothalamus pathways

Envelope contributions to the representation of interaural time difference in the forebrain of barn owls

Birds and mammals use the interaural time difference (ITD) for azimuthal sound localization. While barn owls can use the ITD of the stimulus carrier frequency over nearly their entire hearing range, mammals have to utilize the ITD of the stimulus envelope to extend the upper frequency limit of ITD-based sound localization. ITD is computed and processed in a dedicated neural circuit that consists of two pathways. In the barn owl, ITD representation is more complex in the forebrain than in the midbrain pathway because of the combination of two inputs that represent different ITDs. We speculated that one of the two inputs includes an envelope contribution. To estimate the envelope contribution, we recorded ITD response functions for correlated and anticorrelated noise stimuli in the barn owl's auditory arcopallium. Our findings indicate that barn owls, like mammals, represent both carrier and envelope ITDs of overlapping frequency ranges, supporting the hypothesis that carrier and envelope ITD-based localization are complementary beyond a mere extension of the upper frequency limit.NEW & NOTEWORTHY The results presented in this study show for the first time that the barn owl is able to extract and represent the interaural time difference (ITD) information conveyed by the envelope of a broadband acoustic signal. Like mammals, the barn owl extracts the ITD of the envelope and the carrier of a signal from the same frequency range. These results are of general interest, since they reinforce a trend found in neural signal processing across different species.

EP 50. Correlation between oculomotor changes and atlas-based volumetry in patients with different neurodegenerative Parkinson syndromes

Background Characteristically impaired oculomotor functions are recognized in Parkinsonian syndromes including idiopathic Parkinson disease (PD), Multiple System Atrophy (MSA), Progressive Supranuclear Palsy (PSP) ( Pinkhardt and Kassubek, 2011 ). Atrophy of specific brain structures has been reported in Parkinsonian syndromes ( Brenneis et al., 2007 , Focke et al., 2011 ). The aim of this study was to investigate possible relationships between oculomotor alterations and volumetric alterations in PD, PSP and MSA. Methods Forty-two PD, 18 MSA, and 32 PSP patients together with 26 healthy controls underwent standardized video-oculographic testing and MRI at a clinical 1.5T scanner. Whole-brain based T1-weighted MRI-images were analyzed using atlas-based volumetry ( Kassubek et al., 2011 ). Data of 5 brain structures (forebrain, brainstem, cerebellum, midbrain, pons) and 5 oculomotor parameters (smooth pursuit gain, peak eye velocity, rate of saccadic intrusions, anti-saccade errors) were used for group comparisons in PD, MSA and PSP with healthy controls. Oculomotor parameters were correlated with regional brain volumes in the patients. Results PD patients compared with control showed a significantly increased rate of saccadic intrusions (p). Conclusions The worse the oculomotor performance the lower the regional brain volume, suggesting a relationship between regional brain atrophy and cerebral oculomotor network disturbances. Deficits in eye movement control in PD appear to be characterized by executive abnormalities, whereas oculomotor dysfunctions in MSA and PSP were associated with impaired pontine and midbrain pathways.

Cholinergic Mesopontine Signals Govern Locomotion and Reward through Dissociable Midbrain Pathways

The mesopontine tegmentum, including the pedunculopontine and laterodorsal tegmental nuclei (PPNand LDT), provides major cholinergic inputs to midbrain and regulates locomotion and reward. To delineate the underlying projection-specific circuit mechanisms, we employed optogenetics to controlmesopontine cholinergic neurons at somata and atdivergent projections within distinct midbrain areas.Bidirectional manipulation of PPN cholinergic cell bodies exerted opposing effects on locomotor behavior and reinforcement learning. These motor and reward effects were separable via limiting photostimulation to PPN cholinergic terminals in the ventral substantia nigra pars compacta (vSNc) or tothe ventral tegmental area (VTA), respectively. LDT cholinergic neurons also form connections with vSNc and VTA neurons; however, although photo-excitation of LDT cholinergic terminals in the VTA caused positive reinforcement, LDT-to-vSNc modulation did not alter locomotion or reward. Therefore, the selective targeting of projection-specific mesopontine cholinergic pathways may offer increased benefit in treating movement and addiction disorders.

Effect of Suprachiasmatic Nucleus Lesion on Period2 and C-fos Expression in Habenular Nucleus

The habenular nucleus (Hb) located in the epithalamus is an important connection between the limbic forebrain and midbrain pathway and it regulates physiological activities including reproduction, sleep-wake, body temperature. Hb is anatomically close to the suprachiasmatic nucleus (SCN), the pacemaker of circadian rhythms in mammals. In vivo data showed circadian oscillation of Period2 (Per2) expression in Hb. However, it remains unknown whether the circadian oscillation of Per2 expression is regulated by SCN. We used semi-quantity RT-PCR methods to examine the relative expression of Per2 and c-fos mRNA in the Hb at 13:00 and 1:00 in the LD (light-dark) cycle either SCN was intact or destroyed. The expression of Per2 and c-fos mRNA in the Hb was higher at 13:00 than at 1:00. However, damaging the SCN abolished the difference of Per2 and c-fos mRNA expression at the two time ponits in the Hb, suggesting circadian oscillation of Per2 and c-fos gene in the Hb may be regulated by SCN under in vivo condition.

Chondroitinase improves midbrain pathway reconstruction by transplanted dopamine progenitors in Parkinsonian mice.

Within the adult central nervous system the lack of guidance cues together with the presence of inhibitory molecules produces an environment that is restrictive to axonal growth following injury. Consequently, while clinical trials in Parkinson's disease (PD) patients have demonstrated the capacity of fetal-derived dopamine neurons to survive, integrate and alleviate symptoms, the non-permissive host environment has contributed to the incomplete re-innervation of the target tissue by ectopic grafts, and even more noticeable, the poor reconstruction of the midbrain dopamine pathways following homotopic midbrain grafting. One such inhibitory molecule is the chondroitin sulfate proteoglycan (CSPG), a protein that has been shown to impede axonal growth during development and after injury. Digestion of CSPGs, by delivery of the bacterial enzyme chondroitinase ABC (ChABC), can improve axonal regrowth following a number of neural injuries. Here we examined whether ChABC could similarly improve axonal growth of transplanted dopamine neurons in an animal model of PD. Acute delivery of ChABC, into the medial forebrain bundle, degraded CSPGs along the nigrostriatal pathway. Simultaneous homotopic transplantation of dopaminergic progenitors, into the ventral midbrain of ChABC treated PD mice, had no effect on graft survival but resulted in enhanced axonal growth along the nigrostriatal pathway and reinnervation of the striatum, compared to control grafted mice. This study demonstrates that removal of axonal growth inhibitory molecules could significantly enhance dopaminergic graft integration, thereby holding implications for future approaches in the development of cell replacement therapies for Parkinsonian patients.

Abstract 2018: Elucidating the therapeutic potential of midbrain pathways that impact breast cancer

Abstract Most chemotherapeutic agents for breast cancer have variable efficacy and produce unwanted side effects. While much focus is placed on dissecting the molecular mechanisms contributing to tumor development, the potential role of the brain in regulating tumor progression has not been described in detail. Previous evidence has shown that midbrain activity affects tumor growth and progression. Stimulation of the midbrain periaqueductal grey (PAG) increases metastasis in rats injected with Walker-256 carcinosarcoma cells, and the growth of prolactin-dependent mammary tumors. These findings suggest midbrain pathways play a prominent role in tumorigenesis. These studies, however, did not address the therapeutic potential of blocking PAG output for slowing tumor progression. Therefore, we are studying the mechanisms regulating midbrain-induced tumorigenesis and the therapeutic potential of altering midbrain activity to reduce metastatic activity and tumor growth. A common challenge in neuroscience has been identifying and manipulating specific neuronal populations in the brain. However, significant advances have been made in the field of optogenetics, the integration of optics and genetics, which allows precise control of specific neural pathways in vivo using light. Optogenetics is gaining considerable clinical interest as a novel strategy for treating human neurological disorders due to success observed in rodent and non-primate human models. Therefore, optogenetic alteration of PAG activity for treating breast cancer is plausible. Non-pharmacological, therapeutic strategies aimed at manipulating circuit activity to treat mood and anxiety disorders are already creating enthusiasm. Given that many of these strategies likely impact PAG activity, there is great potential for manipulating the same pathways to treat breast cancer. Before these types of novel strategies can be implemented, we must first delineate the biology of these circuits and their therapeutic potential in animal models of cancer. Thus far, we have identified that muscimol inhibition of PAG activity decreases breast cancer progression in a transgenic mouse model. We are continuing to investigate the distinct input/output mechanisms of the PAG that could be modified to treat breast cancer. Future studies have the potential to reveal novel avenues for targeting and preventing the development of breast cancer via the manipulability of specific neural pathways. Note: This abstract was not presented at the meeting. Citation Format: Madeline Chandra, John Lee, Patrick L. Sheets, Jenifer R. Prosperi. Elucidating the therapeutic potential of midbrain pathways that impact breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2018. doi:10.1158/1538-7445.AM2015-2018

Chemogenetic synaptic silencing of neural circuits localizes a hypothalamus→midbrain pathway for feeding behavior.

Brain function is mediated by neural circuit connectivity, and elucidating the role of connections is aided by techniques to block their output. We developed cell-type-selective, reversible synaptic inhibition tools for mammalian neural circuits by leveraging G protein signaling pathways to suppress synaptic vesicle release. Here, we find that the pharmacologically selective designer Gi-protein-coupled receptor hM4D is a presynaptic silencer in the presence of its cognate ligand clozapine-N-oxide (CNO). Activation of hM4D signaling sharply reduced synaptic release probability and synaptic current amplitude. To demonstrate the utility of this tool for neural circuit perturbations, we developed an axon-selective hM4D-neurexin variant and used spatially targeted intracranial CNO injections to localize circuit connections from the hypothalamus to the midbrain responsible for feeding behavior. This synaptic silencing approach is broadly applicable for cell-type-specific and axon projection-selective functional analysis of diverse neural circuits.

Cocaine Drives Aversive Conditioning via Delayed Activation of Dopamine-Responsive Habenular and Midbrain Pathways

Many strong rewards, including abused drugs, also produce aversive effects that are poorly understood. For example, cocaine can produce aversive conditioning after its rewarding effects have dissipated, consistent with opponent process theory, but the neural mechanisms involved are not well known. Using electrophysiological recordings in awake rats, we found that some neurons in the lateral habenula (LHb), where activation produces aversive conditioning, exhibited biphasic responses to single doses of intravenous cocaine, with an initial inhibition followed by delayed excitation paralleling cocaine's shift from rewarding to aversive. Recordings in LHb slice preparations revealed similar cocaine-induced biphasic responses and further demonstrated that biphasic responses were mimicked by dopamine, that the inhibitory phase depended on dopamine D2-like receptors, and that the delayed excitation persisted after drug washout for prolonged durations consistent with findings in vivo. c-Fos experiments further showed that cocaine-activated LHb neurons preferentially projected to and activated neurons in the rostromedial tegmental nucleus (RMTg), a recently identified target of LHb axons that is activated by negative motivational stimuli and inhibits dopamine neurons. Finally, pharmacological excitation of the RMTg produced conditioned place aversion, whereas cocaine-induced avoidance behaviors in a runway operant paradigm were abolished by lesions of LHb efferents, lesions of the RMTg, or by optogenetic inactivation of the RMTg selectively during the period when LHb neurons are activated by cocaine. Together, these results indicate that LHb/RMTg pathways contribute critically to cocaine-induced avoidance behaviors, while also participating in reciprocally inhibitory interactions with dopamine neurons.

Recurrent Interactions between the Input and Output of a Songbird Cortico-Basal Ganglia Pathway Are Implicated in Vocal Sequence Variability

Complex brain functions, such as the capacity to learn and modulate vocal sequences, depend on activity propagation in highly distributed neural networks. To explore the synaptic basis of activity propagation in such networks, we made dual in vivo intracellular recordings in anesthetized zebra finches from the input (nucleus HVC, used here as a proper name) and output [lateral magnocellular nucleus of the anterior nidopallium (LMAN)] neurons of a songbird cortico-basal ganglia (BG) pathway necessary to the learning and modulation of vocal motor sequences. These recordings reveal evidence of bidirectional interactions, rather than only feedforward propagation of activity from HVC to LMAN, as had been previously supposed. A combination of dual and triple recording configurations and pharmacological manipulations was used to map out circuitry by which activity propagates from LMAN to HVC. These experiments indicate that activity travels to HVC through at least two independent ipsilateral pathways, one of which involves fast signaling through a midbrain dopaminergic cell group, reminiscent of recurrent mesocortical loops described in mammals. We then used in vivo pharmacological manipulations to establish that augmented LMAN activity is sufficient to restore high levels of sequence variability in adult birds, suggesting that recurrent interactions through highly distributed forebrain-midbrain pathways can modulate learned vocal sequences.

Contraction Anisocoria: Segregation, Summation, and Saturation in the Pupillary Pathway

To investigate the neural basis of contraction anisocoria and any implications for assessments using pupillary responses, through analysis of topographic variation in amplitudes of direct and consensual pupil responses. Direct and consensual pupillary contraction amplitudes were analyzed from six studies in which 120 normal subjects were tested with 24 different stimulus variants. The dichoptically presented multifocal stimulus arrays subtended ± 30° of visual field but varied in color (achromatic or yellow), number of test regions (24 to 60/eye), mean regional presentation interval (0.25 to 16 s), and pulse time-course (33 to 150 ms, flickered or steady). The 290 cd/m(2) test-regions were displayed on a 10 cd/m(2) background. Ratios between mean direct and consensual responses were calculated for each region. Results were quantified using multivariate linear analysis. Direct responses within the temporal hemifield were significantly larger than consensual for all stimulus protocols. Across the 24 protocols these differences ranged between 13.8% (t(1415)=3.06, P<0.01) and 27.0% (t(990)=5.72, P<0.0001). Differences in the nasal field were mostly non-significant. Contraction amplitudes varied systematically across the visual field. By contrast, direct/consensual ratios were markedly uniform within each hemifield. The distribution of signal from the pretectal olivary nuclei to each Edinger-Westphal nucleus differs depending on the hemifield being stimulated. A simple model incorporating segregation and summation of afferent signals, and differing saturation of midbrain pathways is proposed. This appears to explain inconsistent observations in the literature and predicates the need for separate assessment of direct and consensual responses at hemifield or better resolution.

Learning processes and the neural analysis of conditioning.

Classical and operant conditioning principles, such as the behavioral discrepancy-derived assumption that reinforcement always selects antecedent stimulus and response relations, have been studied at the neural level, mainly by observing the strengthening of neuronal responses or synaptic connections. A review of the literature on the neural basis of behavior provided extensive scientific data that indicate a synthesis between the two conditioning processes based mainly on stimulus control in learning tasks. The resulting analysis revealed the following aspects. Dopamine acts as a behavioral discrepancy signal in the midbrain pathway of positive reinforcement, leading toward the nucleus accumbens. Dopamine modulates both types of conditioning in the Aplysia mollusk and in mammals. In vivo and in vitro mollusk preparations show convergence of both types of conditioning in the same motor neuron. Frontal cortical neurons are involved in behavioral discrimination in reversal and extinction procedures, and these neurons preferentially deliver glutamate through conditioned stimulus or discriminative stimulus pathways. Discriminative neural responses can reliably precede operant movements and can also be common to stimuli that share complex symbolic relations. The present article discusses convergent and divergent points between conditioning paradigms at the neural level of analysis to advance our knowledge on reinforcement.

The emerging biology of delusions

This article examines a model of how delusions may arise, not just in schizophrenia but also in a number of neurological and psychiatric conditions, through a combination of dysregulated dopamine release from ascending midbrain pathways and reasoning bias. Negative symptoms may also be related to dopamine dysregulation, with the precise mixture of positive and negative symptoms depending on the relative degree of dopamine dysregulation in particular mesocorticolimbic circuits. Evidence for this model is examined, and predictions arising from this model are described.

Pupillographic Investigation of the Relative Afferent Pupillary Defect Associated with a Midbrain Lesion

To identify clinical and pupillographic features of patients with a relative afferent pupillary defect (RAPD) without visual acuity or visual field loss caused by a lesion in the dorsal midbrain. Experimental study. Four patients with a dorsal midbrain lesion who had normal visual fields and a clinically detectable RAPD. The pupil response from full-field and hemifield light stimulation over a range of light intensities was measured by computerized binocular pupillography. The mean of the direct and consensual pupil response to full-field and hemifield light stimulation was plotted as a function of stimulus light intensity. All 4 subjects showed decreased pupillographic responses at all intensities to full-field light stimulation in the eye with the clinical RAPD. The pupillographic responses to hemifield stimulation showed a homonymous pattern of deficit on the side ipsilateral to the RAPD, similar to that observed in a previously reported patient with an optic tract lesion. The basis of a midbrain RAPD is the nasal-temporal asymmetry of pupillomotor input that becomes manifest when a unilateral postchiasmal lesion interrupts homonymously paired fibers traveling in the contralateral optic tract or midbrain pathway to the pupillomotor center, respectively. The pupillographic characteristics of an RAPD resulting from a dorsal midbrain lesion thus resemble those of an RAPD resulting from a unilateral optic tract lesion, but without the homonymous visual field defect. The author(s) have no proprietary or commercial interest in any materials discussed in this article.