Corticostriatal circuitry

Corticostriatal connections play a central role in developing appropriate goal-directed behaviors, including the motivation and cognition to develop appropriate actions to obtain a specific outcome. The cortex projects to the striatum topographically. Thus, different regions of the striatum have been associated with these different functions: the ventral striatum with reward; the caudate nucleus with cognition; and the putamen with motor control. However, corticostriatal connections are more complex, and interactions between functional territories are extensive. These interactions occur in specific regions in which convergence of terminal fields from different functional cortical regions are found. This article provides an overview of the connections of the cortex to the striatum and their role in integrating information across reward, cognitive, and motor functions. Emphasis is placed on the interface between functional domains within the striatum.     

Development of neocortical circuitry: Quantitative ultrastructural analysis of putative monoaminergic synapses

The distribution, numbers and morphology of presumed monoaminergic (MA) synapses were examined in somatosensory cortex of neonatal rats and mice (newborn to 16 days of age). MA synapses were identified using an ultrastructural cytochemical marker, 5-hydroxydopamine (5-OHDA), which results in the appearance of small granular vesicles (SGV) in their presynaptic terminals. From birth to 7 days of age, 20--30% of all synapses sampled in somatosensory cortex contain SGVs. However, few SGV synapses are seen in 8-day-old cortex and by 12 days of age, SGVs are no longer detectable in cortex. A specific laminar distribution for these SGV synapses -- which is distinct from the overall synaptic distribution -- is first seen at 3 days of age and is essentially unchanged until 7 days postnatally. During this entire period, the SGV synapses predominate in the primordium of layer IV, where they account for 50--70% of all synapses. Morphometric analysis of SGV synapses indicates that there are differences in junctional symmetry, vesicle shape and configuration of the contact zone between SGV and non-SGV synapses, as well as between SGV synapses themselves in the various cortical layers. The laminar distribution and morphological characteristics of SGV synapses suggest that the MA projection to neocortex exhibits a high degree of spatial specificity during its ingrowth. Also, the relatively high proportion of SGV synapses in the first postnatal week may reflect a potent influence exerted by the MA inputs on immature neocortex. The decreased numerical density of SGV synapses after 7 days of age is probably due to the development of the blood-brain barrier to 5-OHDA.     

Developmental specification of metabolic circuitry

The hypothalamus contains a core circuitry that communicates with the brainstem and spinal cord to regulate energy balance. Because metabolic phenotype is influenced by environmental variables during perinatal development, it is important to understand how these neural pathways form in order to identify key signaling pathways that are responsible for metabolic programming. Recent progress in defining gene expression events that direct early patterning and cellular specification of the hypothalamus, as well as advances in our understanding of hormonal control of central neuroendocrine pathways, suggest several key regulatory nodes that may represent targets for metabolic programming of brain structure and function. This review focuses on components of central circuitry known to regulate various aspects of energy balance and summarizes what is known about their developmental neurobiology within the context of metabolic programming.     

The neurochemical circuitry of schizophrenia

The aim of this paper is to describe the connectivity of some basic neuronal circuits assumed to be causally related to the generation of symptoms in schizophrenia. The role of various transmitter substances like dopamine, glutamate, serotonin and GABA can be explained by the circuitry of the respective pathways in the brain. Activating and inhibiting loops that are coupled can shift into an imbalance that might result in the generation of positive and negative symptoms. Finally, the paper draws attention to the hypothesis that extrasynaptic receptors might play an important role in schizophrenia. The paper shows that thinking in loops might be an efficient strategy for obtaining a functional understanding of the neuronal circuitry involved in the complex symptomatology of schizophrenia. Those models help us to understand the action of antipsychotic medications.     

Frontal-subcortical circuitry and behavior

The neuropsychiatric manifestations of neurodegenerative diseases are closely linked to neurocircuitry defects. Frontal-subcortical circuits, in particular, are effector mechanisms that allow the organism to act on its environment. In this paper, we present the three main frontal-subcortical circuits: the dorsolateral prefrontal circuit allows the organization of information to facilitate a response; the anterior cingulate circuit is required for motivated behavior; and the orbitofrontal circuit allows the integration of limbic and emotional information into behavioral responses. Impaired executive functions, apathy, and impulsivity are hallmarks of frontal-subcortical circuit dysfunction. A variety of other neuropsychiatric disorders, such as Tourette's syndrome, Huntington's disease, obsessive-compulsive disorder, attention-deficit/hyperactivity disorder, schizophrenia, and mood disorders may result from disturbances that have a direct or indirect impact on the integrity or functioning of these loops.     

Pharmacological analysis of cortical circuitry

The cortical circuitry of the visual cortex has been worked out in great detail. Anatomical investigations reveal stereotyped connections within cortical columns and specific long-range connections between distant columns. Pharmacological techniques for blocking the activity in individual cortical layers or columns allow the microdissection of the cortical circuit. These studies could relate specific functional roles to particular cortical connections.     

Estrogen-induced remodeling of hypothalamic neural circuitry

For decades, sexual behavior has been a valuable model system for behavioral neuroscientists studying the neural basis of motivated behaviors. One striking example of a change in motivation is the binary switch in sexual receptivity that occurs during the estrous cycle in female rats. Investigations of the neural basis of this change in behavior have fundamentally advanced our understanding of both behaviorally relevant neural pathways and basic mechanisms of steroid action in the brain. These advances have made this behavioral model system a staple of neuroendocrinology. A challenge that remains before us, given our current understanding of the circuitry and chemistry, is to develop a coherent model of how neural plasticity in the hypothalamus contributes to the dependence of this behavior on motivational state. This review will focus on the ventromedial nucleus of the hypothalamus, especially its ventrolateral subdivision. First, the anatomical, neurochemical, and functional aspects of the macro- and microcircuitry of this brain region will be discussed, followed by a discussion of the likely mechanisms of estrogen action within the ventrolateral VMH. Then, the evidence for estrogen-induced neural plasticity will be considered, including a comparison with the effects of estrogen on synaptic organization in other brain regions. Finally, a working model of neural plasticity within the ventrolateral VMH microcircuitry will be presented as a starting point for future experiments to verify or, more likely, revise and expand.     

Cultural objects modulate reward circuitry

Using event-related fMRI we investigated the rewarding properties of cultural objects (cars) signaling wealth and social dominance. It has been shown recently that reward mechanisms are involved in the regulation of social relations like dominance and social rank. Based on evolutionary considerations we hypothesized that sports cars in contrast to other categories of cars, e.g. limousines and small cars, are strong social reinforcers and would modulate the dopaminergic reward circuitry. Twelve healthy male subjects were studied with fMRI while viewing photographs of different car classes followed by an attractivity rating. Behaviorally sports cars were rated significantly more attractive than limousines and small cars. Our fMRI results revealed significantly more activation in ventral striatum, orbitofrontal cortex, anterior cingulate and occipital regions for sports cars in contrast to other categories of cars. We could thus demonstrate that artificial cultural objects associated with wealth and social dominance elicit activation in reward-related brain areas.     

Feeding signals and brain circuitry

Food intake is a major physiological function in animals and must be entrained to the circadian oscillations in food availability. In the last two decades a growing number of reports have shed light on the hormonal, cellular and molecular mechanisms involved in the regulation of food intake. Brain areas located in the hypothalamus have been shown to play a pivotal role in the regulation of energy metabolism, controlling energy balance. In these areas, neuronal plasticity has been reported that is dependent upon key hormones, such as leptin and ghrelin, that are produced by peripheral organs. This review will provide an overview of recent discoveries relevant to understanding these issues.     

Corticostriatal circuitry mediates fast-track visual categorization

Previous studies have shown that briefly presented natural scenes containing non-animals elicited more negative potentials than images with animals even at 150 ms after stimulus onset (dN150). Cognitive models suggest that both feed-forward and feature weighting processes are involved in the rapid categorization of complex natural scenes. Here we examined the possible neuronal substrates of this model. Patients with Alzheimer's disease (AD) exhibited a delayed dN150, but in their case non-animals evoked more negative potentials similarly to the controls (presence of dN150). In contrast, in patients with Parkinson's disease (PD) animal and non-animal stimuli elicited nearly identical early responses (absence of dN150). The results indicate that when cortico-cortical pathways mediating feed-forward mechanisms are impaired (as in the case of AD), dN150 appears later, while in the case of corticostriatal dysfunctions (as in the case of PD) no differential response is present. This supports the hypothesis that corticostriatal circuits mediate perceptual feature weighting and integration in complex situations requiring categorical judgements.     

Cannabinoid modulation of limbic forebrain noradrenergic circuitry

Both the endocannabinoid and noradrenergic systems have been implicated in neuropsychiatric disorders. Importantly, low levels of norepinephrine are seen in patients with depression, and antagonism of the cannabinoid receptor type 1 (CB1R) is able to induce depressive symptoms in rodents and humans. Whether the interaction between the two systems is important for the regulation of these behaviors is not known. In the present study, adult male Sprague–Dawley rats were acutely or chronically administered the CB1R synthetic agonist WIN 55,212‐2, and α2A and β1 adrenergic receptors (AR) were quantified by Western blot. These AR have been shown to be altered in a number of psychiatric disorders and following antidepressant treatment. CB1R agonist treatment induced a differential decrease in α2A‐ and β1‐ARs in the nucleus accumbens (Acb). Moreover, to assess long‐lasting changes induced by CB1R activation, some of the chronically treated rats were killed 7 days following the last injection. This revealed a persistent effect on α2A‐AR levels. Furthermore, the localization of CB1R with respect to noradrenergic profiles was assessed in the Acb and in the nucleus of the solitary tract (NTS). Our results show a significant topographic distribution of CB1R and dopamine beta hydroxylase immunoreactivities (ir) in the Acb, with higher co‐localization observed in the NTS. In the Acb, CB1R‐ir was found in terminals forming either symmetric or asymmetric synapses. These results suggest that cannabinoids may modulate noradrenergic signaling in the Acb, directly by acting on noradrenergic neurons in the NTS or indirectly by modulating inhibitory and excitatory input in the Acb.     

Interneurons and triadic circuitry of the thalamus

The thalamus is strategically placed to control the flow of information to cortex and thus conscious perception. A key player in this control is a local GABAergic interneuron that inhibits relay cells. This interneuron is especially interesting because, in addition to a conventional axonal output, most of its output is via distal dendrites. The latter seem to be electrotonically and thus functionally isolated from the soma and axon, and they enter into complex synaptic arrangements. It is proposed that, because of special synaptic properties of its dendritic outputs, this local GABAergic interneuron of the thalamus provides gain control for the relay cell and thereby keeps relay of information to cortex within a fairly linear regime.     

The circuitry of the enteric nervous system

Abstract A brief account of the aquisition of knowledge of the enteric nervous system and the ways in which technological developments have contributed to analysis of the reflex circuits is presented. The review concentrates on the motility controlling circuits in the small intestine of the guinea-pig, where much more is known than for any other region or species. In this region, the basic circuit is known. Primary sensory neurons connect monosynaptically to motor neurons, and also make connections via chains of interneurons, which in turn provide outputs to the motor neurons. The ascending excitatory and descending inhibitory reflexes are manifested through these circuits. Sufficient details of the functions and connections of all neuron classes are available to permit activity in the reflex pathways to be realistically simulated in a computer model, which is briefly described.     

Neurochemical studies on the mesolimbic circuitry of antinociception

Previous studies using the technique of microinjection into brain nuclei indicated that the periaqueductal gray (PAG), nucleus accumbens, habenula and amygdala play an essential role in pain modulation and that these nuclei possibly act through a ‘mesolimbic neural loop‘ to exert an analgesic effect, in which Met-enkephalin (MEK) and β-endorphin (β-EP) have been implicated as the two major opioid peptides involved in antinociception. In the present study performed in rabbits, intracranial microinjection was supplemented with push-pull perfusion and radioimmunoassay to determine whether the release of enkephalins (ENK) and β-EP was increased in these nuclei when the putative neural circuit was activated by morphine administered into one of the nuclei. The results showed: (1) microinjection of morphine into the PAG increased the release of ENK and β-EP in the N. accumbens, and vice versa; (2) microinjection of morphine into the N. accumbens increased the release of ENK and β-EP in the amygdala, and vice versa; (3) morphine microinjected into the PAG caused an increase in the release of ENK and β-EP in the amygdala and vice versa, although the release of ENK in PAG was statistically not significant. These results indicate that PAG, N. accumbens and amygdala are connected in a network served by a positive feedback circuitry.     

Neuroimaging of emotional brain circuitry in bipolar disorder

Abnormalities in the regulation of emotion and motivational behavior are core features of bipolar disorder (BD) implicating the brain structures that subserve these functions. Converging neuroimaging evidence supports the involvement in BD of a neural system comprised of ventral prefrontal cortex, amygdala, and ventral striatum. Neuroimaging studies demonstrate abnormalities in both the structure and function of these brain regions. Findings in amygdala and ventral striatum in adolescents with BD suggest a neurodevelopmental trajectory for the appearance of regional abnormalities in this neural system. Preliminary studies suggest that mood-stabilizing medications may provide beneficial effects for the structure and functioning of this circuitry. New research directions, including those that integrate genetic studies with neuroimaging research, may provide important insights into the pathophysiologic mechanisms contributing to BD, and point to new strategies for its detection and treatment.     

Neural circuitry underlying voluntary suppression of sadness.

BACKGROUND: The ability to voluntarily self-regulate negative emotion is essential to a healthy psyche. Indeed, a chronic incapacity to suppress negative emotion might be a key factor in the genesis of depression and anxiety. Regarding the neural underpinnings of emotional self-regulation, a recent functional neuroimaging study carried out by our group has revealed that the dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex are involved in voluntary suppression of sexual arousal. As few things are known, still, with respect to the neural substrate underlying volitional self-regulation of basic emotions, here we used functional magnetic resonance imaging to identify the neural circuitry associated with the voluntary suppression of sadness. METHODS: Twenty healthy female subjects were scanned during a Sad condition and a Suppression condition. In the Sad condition, subjects were instructed to react normally to sad film excerpts whereas, in the Suppression condition, they were asked to voluntarily suppress any emotional reaction in response to comparable stimuli. RESULTS: Transient sadness was associated with significant loci of activation in the anterior temporal pole and the midbrain, bilaterally, as well as in the left amygdala, left insula, and right ventrolateral prefrontal cortex (VLPFC) (Brodmann area [BA] 47). Correlational analyses carried out between self-report ratings of sadness and regional blood oxygen level dependent (BOLD) signal changes revealed the existence of positive correlations in the right VLPFC (BA 47), bilaterally, as well as in the left insula and the affective division of the left anterior cingulate gyrus (BA 24/32). In the Suppression condition, significant loci of activation were noted in the right DLPFC (BA 9) and the right orbitofrontal cortex (OFC) (BA 11), and positive correlations were found between the self-report ratings of sadness and BOLD signal changes in the right OFC (BA 11) and right DLPFC (BA 9). CONCLUSIONS: These results confirm the key role played by the DLPFC in emotional self-regulation. They also indicate that the right DLPFC and right OFC are components of a neural circuit implicated in voluntary suppression of sadness.     

Localizing sadness activation within the subgenual cingulate in individuals: a novel functional MRI paradigm for detecting individual differences in the neural circuitry underlying depression

Variations in frontal lobe (FL) functional anatomy, especially the subgenual cingulate gyrus (SGC) suggest that mapping on an individual rather than group level may give greater insight regarding dysregulation of the neural circuitry involved in depression, as well as potentially provide more specific or individualized treatment plans for depressed patients. We designed a functional MRI task capable of imaging FL activity in individuals, including the SGC region, using a transient sadness paradigm. We sought to develop a method that may better detect individual differences of FL subregions related to sadness, since this region has been implicated to show dysregulation in depression. The task was based on a block design that also accommodates individual differences in responsivity to a sadness induction paradigm. Individual differences from nine non-depressed healthy volunteers were analyzed. We also performed functional connectivity analyses to further characterize our findings to the networks associated with the SGC in each individual. The study was designed to account for individual variation rather than using a true experimental design; therefore, no control group was necessary. As expected, due to inter-individual variability, the specific site of SGC activation during sadness varied across individuals. Activation was also observed in other brain regions consistent with other studies of induced sadness and depression. Patterns of functional connectivity to the SGC also highlighted neural circuits known to subserve sadness and depression. This task promises to more precisely localize a given individual’s functional organization of the brain circuitry underlying sadness, and potentially depression, in an efficient, standardized way. This task could potentially aid in providing individualized targets in the treatment of depression.     

Neural circuitry of the kidney: NO-containing neurons

The neurons synthesizing nitric oxide (NO) that are part of the renal sympathetic pathways were located by double-staining for the neuronal isoform of nitric oxide synthase (nNOS) using immunocytochemistry to identify NO-synthesizing neurons and transneuronal tracing following infection of the left kidney with pseudorabies virus (PRV). Following kidney injection with PRV, the animals survived 4-day post-inoculation prior to sacrifice and tissue processing. PRV-infected neurons that double-stained for nNOS were found in the paraventricular hypothalamic nucleus (PVN), the raphe obscurus nucleus (ROb), the ventromedial medulla (VMM), the rostral ventrolateral medulla (rVLM) and the A5 cell group. In the thoracolumbar spinal cord, nNOS neurons co-localized with PRV-infected cells in the dorsal horn in laminae I, III-V ipsilateral to the injected kidney and in lamina X, the intermediolateral cell column, the lateral funiculus, the intercalated nucleus and the central autonomic area. We conclude that NO synthesizing cells may significantly affect renal autonomic pathways in the rat by interacting with the renal sensory and sympathomotor circuitry at multiple sites.