Waxholm Space atlas of the rat brain: a 3D atlas supporting data analysis and integration.

Volumetric brain atlases are increasingly used to integrate and analyze diverse experimental neuroscience data acquired from animal models, but until recently a publicly available digital atlas with complete coverage of the rat brain has been missing. Here we present an update of the Waxholm Space rat brain atlas, a comprehensive open-access volumetric atlas resource. This brain atlas features annotations of 222 structures, of which 112 are new and 57 revised compared to previous versions. It provides a detailed map of the cerebral cortex, hippocampal region, striatopallidal areas, midbrain dopaminergic system, thalamic cell groups, the auditory system and main fiber tracts. We document the criteria underlying the annotations and demonstrate how the atlas with related tools and workflows can be used to support interpretation, integration, analysis and dissemination of experimental rat brain data.

Organization of the Anterior Limb of the Internal Capsule in the Rat.

Dysfunction of the orbitofrontal (OFC) and anterior cingulate (ACC) cortices has been linked with several psychiatric disorders, including obsessive-compulsive disorder, major depressive disorder, posttraumatic stress disorder, and addiction. These conditions are also associated with abnormalities in the anterior limb of the internal capsule, the white matter (WM) bundle carrying ascending and descending fibers from the OFC and ACC. Furthermore, deep-brain stimulation (DBS) for psychiatric disorders targets these fibers. Experiments in rats provide essential information on the mechanisms of normal and abnormal brain anatomy, including WM composition and perturbations. However, whereas descending prefrontal cortex (PFC) fibers in primates form a well defined and topographic anterior limb of the internal capsule, the specific locations and organization of these fibers in rats is unknown. We address this gap by analyzing descending fibers from injections of an anterograde tracer in the rat ACC and OFC. Our results show that the descending PFC fibers in the rat form WM fascicles embedded within the striatum. These bundles are arranged topographically and contain projections, not only to the striatum, but also to the thalamus and brainstem. They can therefore be viewed as the rat homolog of the primate anterior limb of the internal capsule. Furthermore, mapping these projections allows us to identify the fibers likely to be affected by experimental manipulations of the striatum and the anterior limb of the internal capsule. These results are therefore essential for translating abnormalities of human WM and effects of DBS to rodent models.SIGNIFICANCE STATEMENT Psychiatric diseases are linked to abnormalities in specific white matter (WM) pathways, and the efficacy of deep-brain stimulation relies upon activation of WM. Experiments in rodents are necessary for studying the mechanisms of brain function. However, the translation of results between primates and rodents is hindered by the fact that the organization of descending WM in rodents is poorly understood. This is especially relevant for the prefrontal cortex, abnormal connectivity of which is central to psychiatric disorders. We address this gap by studying the organization of descending rodent prefrontal pathways. These fibers course through a subcortical structure, the striatum, and share important organization principles with primate WM. These results allow us to model primate WM effectively in the rodent.

Heterogeneous neuronal activity in the lateral habenula after short- and long-term cocaine self-administration in rats.

Cocaine addiction is thought to be the result of drug-induced functional changes in a neural network implicated in emotions, learning and cognitive control. Recent studies have implicated the lateral habenula (LHb) in drug-directed behavior, especially its aversive aspects. Limited cocaine exposure has been shown to alter neuronal activity in the LHb, but the impact of long-term drug exposure on habenula function has not been determined. Therefore, using c-fos as a marker, we here examined neuronal activity in LHb in rats that self-administered cocaine for either 10 or 60 days. Both the density of labeled cells and the cellular labeling intensity were measured in the lateral (LHbL) and medial (LHbM) parts of LHb. After 10 days of cocaine self-administration, both the density and intensity of c-fos-positive cells were significantly increased in LHbL, but not LHbM, while after 60 days, an increased density (but not intensity) of labeled neurons in both LHbL and LHbM was observed. Most c-fos-labeled neurons were glutamatergic. In addition, we found increased GAD65 expression after 10 but not 60 days of cocaine self-administration in the rostral mesencephalic tegmental nucleus. These data shed light on the complex temporal dynamics by which cocaine self-administration alters activity in LHb circuitry, which may play an important role in the descent to compulsive drug use as a result of prolonged cocaine-taking experience.

Mesencephalic dopamine neurons interfacing the shell of nucleus accumbens and the dorsolateral striatum in the rat.

Parallel corticostriatonigral circuits have been proposed that separately process motor, cognitive, and emotional-motivational information. Functional integration requires that interactions exist between neurons participating in these circuits. This makes it imperative to study the complex anatomical substrate underlying corticostriatonigral circuits. It has previously been proposed that dopaminergic neurons in the ventral mesencephalon may play a role in this circuit interaction. Therefore, we studied in rats convergence of basal ganglia circuits by depositing an anterograde neuroanatomical tracer into the ventral striatum together with a retrograde fluorescent tracer ipsilaterally in the dorsolateral striatum. In the mesencephalon, using confocal microscopy, we looked for possible appositions of anterogradely labeled fibers and retrogradely labeled neurons, "enhancing" the latter via intracellular injection of Lucifer Yellow. Tyrosine hydroxylase (TH) immunofluorescence served to identify dopaminergic neurons. In neurophysiological experiments, we combined orthodromic stimulation in the medial ventral striatum with recording from ventral mesencephalic neurons characterized by antidromic stimulation from the dorsal striatum. We observed terminal fields of anterogradely labeled fibers that overlap populations of retrogradely labeled nigrostriatal cell bodies in the substantia nigra pars compacta and lateral ventral tegmental area (VTA), with numerous close appositions between boutons of anterogradely labeled fibers and nigrostriatal, TH-immunopositive neurons. Neurophysiological stimulation in the medial ventral striatum caused inhibition of dopaminergic nigrostriatal neurons projecting to the ventrolateral striatal territory. Responding nigrostriatal neurons were located in the medial substantia nigra and adjacent VTA. Our results strongly suggest a functional link between ventromedial, emotional-motivational striatum, and the sensorimotor dorsal striatum via dopaminergic nigrostriatal neurons.

The rat prefrontostriatal system analyzed in 3D: evidence for multiple interacting functional units.

Previous studies in monkeys disclosed a specific arrangement of corticostriatal projections. Prefrontal and premotor areas form dense projection fields surrounded by diffuse terminal areas extending outside the densely innervated region and overlapping with projections from other areas. In this study, the mode of prefrontostriatal innervation was analyzed in rats using a 3D approach. Following injections of tracers in defined cortical areas, 3D maps from individual cases were elaborated and combined into a global 3D map allowing us to define putative overlaps between projection territories. In addition to providing a detailed 3D mapping of the topographic representation of prefrontal cortical areas in the rat striatum, the results stress important similarities between the rodent and primate prefrontostriatal projections. They share the dual pattern of focal and diffuse corticostriatal projections. Moreover, besides segregated projections consistent with parallel processing, the interweaving of projection territories establishes specific patterns of overlaps spatially organized along the dorsoventral, mediolateral, and anteroposterior striatal axis. In particular, the extensive striatal projection fields from the prelimbic and anterior cingulate areas, which partly overlap the terminal fields from medial, orbital, and lateral prefrontal cortical areas, provide putative domains of convergence for integration between reward, cognitive, and motor processes.

Stage-dependent nigral neuronal loss in incidental Lewy body and Parkinson's disease.

To gain a better understanding of the significance of α-synuclein pathological conditions during disease progression in Parkinson's disease, we investigated whether 1) nigral neuronal loss in incidental Lewy body disease and Parkinson's disease donors is associated with the local burden α-synuclein pathological conditions during progression of pathological conditions; 2) the burden and distribution of α-synuclein pathological conditions are related to clinical measures of disease progression. Post-mortem tissue and medical records of 24 Parkinson's disease patients, 20 incidental Lewy body disease donors, and 12 age-matched controls were obtained from the Netherlands Brain Bank for morphometric analysis. We observed a 20% decrease in nigral neuronal cell density in incidental Lewy body disease compared with controls. Nigral neuronal loss (12%) was already observed before the appearance α-synuclein aggregates. The progression from Braak α-synuclein stage 3 to 4 was associated with a significant decline in neuronal cell density (46%). Nigral neuronal loss increased with later Braak α-synuclein stages but did not vary across consecutive Braak α-synuclein stages. We observed a negative correlation between neuronal density and local α-synuclein burden in the substantia nigra of Parkinson's disease patients (ρ = -0.54), but no relationship with Hoehn & Yahr stage or disease duration. In conclusion, our findings cast doubt on the pathogenic role of α-synuclein aggregates in elderly, but do suggest that the severity of neurodegeneration and local burden of α-synuclein pathological conditions are closely coupled during disease progression in Parkinson's disease.

Limbic and motor circuits involved in symmetry behavior in Tourette's syndrome.

OBJECTIVE: The need for symmetry and ordering objects related to a "just right"-feeling is a common symptom in Tourette's syndrome (TS) and resembles symmetry behavior in obsessive-compulsive disorder, but its pathophysiology is unknown. We used a symptom provocation paradigm to investigate the neural correlates of symmetry behavior in TS and hypothesized the involvement of frontal-striatal and limbic brain areas. METHODS: Pictures of asymmetrically and symmetrically arranged objects were presented in randomized blocks (4 blocks of each condition) to 14 patients with TS and 10 matched healthy controls (HC). A H2 15O positron emission tomography scan was acquired during each stimulus block, resulting in 8 scans per subject. After each scan, state anxiety and symmetry behavior (the urge to rearrange objects) were measured using a visual analogue scale. RESULTS: During the asymmetry condition, TS patients showed increased regional cerebral blood flow (rCBF) in the anterior cingulate cortex, supplementary motor area, and inferior frontal cortex, whereas HC showed increased rCBF in the visual cortex, primary motor cortex, and dorsal prefrontal cortex. Symmetry ratings during provocation correlated positively with orbitofrontal activation in the TS group and sensorimotor activation in the HC group, and negatively with dorsal prefrontal activity in HC. CONCLUSIONS: Results suggest that both motor and limbic circuits are involved in symmetry behavior in TS. Motor activity may relate to an urge to move or perform tics, and limbic activation may indicate that asymmetry stimuli are salient for TS patients. In contrast, symmetry provocation in HC resulted in activation of brain regions implicated in sensorimotor function and cognitive control.

The intralaminar thalamus: a review of its role as a target in functional neurosurgery.

The intralaminar thalamus, in particular the centromedian-parafascicular complex, forms a strategic node between ascending information from the spinal cord and brainstem and forebrain circuitry that involves the cerebral cortex and basal ganglia. A large body of evidence shows that this functionally heterogeneous region regulates information transmission in different cortical circuits, and is involved in a variety of functions, including cognition, arousal, consciousness and processing of pain signals. Not surprisingly, the intralaminar thalamus has been a target area for (radio)surgical ablation and deep brain stimulation (DBS) in different neurological and psychiatric disorders. Historically, ablation and stimulation of the intralaminar thalamus have been explored in patients with pain, epilepsy and Tourette syndrome. Moreover, DBS has been used as an experimental treatment for disorders of consciousness and a variety of movement disorders. In this review, we provide a comprehensive analysis of the underlying mechanisms of stimulation and ablation of the intralaminar nuclei, historical clinical evidence, and more recent (experimental) studies in animals and humans to define the present and future role of the intralaminar thalamus as a target in the treatment of neurological and psychiatric disorders.

Diagnostic cerebrospinal fluid biomarkers for Parkinson's disease: a pathogenetically based approach.

The inaccuracy of the early diagnosis of Parkinson's disease (PD) has been a major incentive for studies aimed at the identification of biomarkers. Brain-derived cerebrospinal fluid (CSF) proteins are potential biomarkers considering the major role that proteins play in PD pathogenesis. In this review, we discuss the current hypotheses about the pathogenesis of PD and identify the most promising candidate biomarkers among the CSF proteins studied so far. The list of potential markers includes proteins involved in various pathogenetic processes, such as oxidative stress and protein aggregation. This list will undoubtedly grow in the near future by application of CSF proteomics and subsequent validation of identified proteins. Probably a single biomarker will not suffice to reach high sensitivity and specificity, because PD is pathogenetically heterogeneous and shares etiological factors with other neurodegenerative diseases. Furthermore, identified candidate biomarkers will have to be thoroughly validated before they can be implemented as diagnostic aids.

The major symptom dimensions of obsessive-compulsive disorder are mediated by partially distinct neural systems.

Obsessive-compulsive disorder (OCD) is a clinically heterogeneous disorder characterized by multiple, temporally stable symptom dimensions. Preliminary functional neuroimaging studies suggest that these symptom dimensions may have distinct neural substrates. Whole-brain voxel-based morphometry was used to examine the common and distinct neuroanatomical (structural) substrates of the major symptom dimensions of OCD. First, we compared 55 medication-free patients with OCD and 50 age-matched healthy control subjects. Multiple regression analyses were then used to examine the relationship between global and regional grey matter (GM) and white matter (WM) volumes and symptom dimension scores within the patient group. OCD patients showed decreased GM volume in left lateral orbitofrontal (BA47), left inferior frontal (BA44/45), left dorsolateral prefrontal (BA9) and right medial prefrontal (BA10) cortices and decreased bilateral prefrontal WM volume. Scores on the 'symmetry/ordering' dimension were negatively correlated with 'global' GM and WM volumes. Scores on the 'contamination/washing' dimension were negatively correlated with 'regional' GM volume in bilateral caudate nucleus and WM volume in right parietal region. Scores on the 'harm/checking' dimension were negatively correlated with regional GM and WM volume in bilateral temporal lobes. Scores on the 'symmetry/ordering' dimension were negatively correlated with regional GM volume in right motor cortex, left insula and left parietal cortex and positively correlated with bilateral temporal GM and WM volume. The results remained significant after controlling for age, sex, educational level, overall illness severity, global WM and GM volumes and excluding patients with comorbid depression. The reported symptom dimension-specific GM and WM alterations support the hypothesis that OCD is an etiologically heterogeneous disorder, with both overlapping and distinct neural correlates across symptom dimensions. These results have clear implications for the current neuroanatomical model of OCD and call for a substantial revision of such model which takes into account the heterogeneity of the disorder.

On the pathophysiology and treatment of akinetic mutism.

Akinetic mutism (AM) is a rare neurological disorder characterized by the presence of an intact level of consciousness and sensorimotor capacity, but with a simultaneous decrease in goal-directed behavior and emotions. Patients are in a wakeful state of profound apathy, seemingly indifferent to pain, thirst, or hunger. It represents the far end within the spectrum of disorders of diminished motivation. In recent years, more has become known about the functional roles of neurocircuits and neurotransmitters associated with human motivational behavior. More specific, there is an increasing body of behavioral evidence that links specific damage of functional frontal-subcortical organization to the occurrence of distinct neurological deficits. In this review, we combine evidence from lesion studies and neurophysiological evidence in animals, imaging studies in humans, and clinical investigations in patients with AM to form an integrative theory of its pathophysiology. Moreover, the specific pharmacological interventions that have been used to treat AM and their rationales are reviewed, providing a comprehensive overview for use in clinical practice.

The orbital cortex in rats topographically projects to central parts of the caudate-putamen complex.

Disturbances of the orbitofrontal-striatal pathways in humans have been associated with several psychopathologies including obsessive-compulsive disorder and drug addiction. In nonhuman primates, different subareas of the orbitofrontal cortex project topographically to central and ventromedial parts of the striatum. Relatively little is known about the anatomical organization of the rat orbital cortex while there is a growing interest in this cortical area from a functional and behavioral point of view. The aim of the present neuroanatomical tracing study was to determine in rats the striatal target area of the projections of the orbital cortex as well as the topographical organization within these projections. To this end, anterograde tracers were injected in the different cytoarchitectonically distinct subareas of the orbital cortex. The results show that the individual orbital areas, i.e. medial orbital area, ventral orbital area, ventrolateral orbital area and lateral orbital area, project to central parts of the caudate-putamen, exhibiting a mediolateral and, to a lesser degree, rostrocaudal topographical arrangement. Orbital projections avoid the most dorsal, as well as rostral and caudal parts of the caudate-putamen. Terminal fields from cytoarchitectonically different areas show a considerable overlap. Superficial cortical layers project preferentially to the striatal matrix, deep layers to the patch compartment. The projections from the ventrolateral orbital area are strongest and occupy the most extensive striatal area. In addition to projections to the caudate-putamen, the ventrolateral, lateral and dorsolateral orbital areas have a scarce projection to the most lateral part of the nucleus accumbens shell in the ventral striatum. In contrast to nonhuman primates, the remainder of the rat nucleus accumbens is virtually free of orbital projections.

Damaged fiber tracts of the nucleus basalis of Meynert in Parkinson's disease patients with visual hallucinations.

Damage to fiber tracts connecting the nucleus basalis of Meynert (NBM) to the cerebral cortex may underlie the development of visual hallucinations (VH) in Parkinson's disease (PD), possibly due to a loss of cholinergic innervation. This was investigated by comparing structural connectivity of the NBM using diffusion tensor imaging in 15 PD patients with VH (PD + VH), 40 PD patients without VH (PD - VH), and 15 age- and gender-matched controls. Fractional anisotropy (FA) and mean diffusivity (MD) of pathways connecting the NBM to the whole cerebral cortex and of regional NBM fiber tracts were compared between groups. In PD + VH patients, compared to controls, higher MD values were observed in the pathways connecting the NBM to the cerebral cortex, while FA values were normal. Regional analysis demonstrated a higher MD of parietal (p = 0.011) and occipital tracts (p = 0.027) in PD + VH, compared to PD - VH patients. We suggest that loss of structural connectivity between the NBM and posterior brain regions may contribute to the etiology of VH in PD. Future studies are needed to determine whether these findings could represent a sensitive marker for the hypothesized cholinergic deficit in PD + VH patients.

Putting a spin on the dorsal-ventral divide of the striatum.

Since its conception three decades ago, the idea that the striatum consists of a dorsal sensorimotor part and a ventral portion processing limbic information has sparked a quest for functional correlates and anatomical characteristics of the striatal divisions. But this classic dorsal-ventral distinction might not offer the best view of striatal function. Anatomy and neurophysiology show that the two striatal areas have the same basic structure and that sharp boundaries are absent. Behaviorally, a distinction between dorsolateral and ventromedial seems most valid, in accordance with a mediolateral functional zonation imposed on the striatum by its excitatory cortical, thalamic and amygdaloid inputs. Therefore, this review presents a synthesis between the dorsal-ventral distinction and the more mediolateral-oriented functional striatal gradient.

Frontal-striatal dysfunction during planning in obsessive-compulsive disorder.

BACKGROUND: Dysfunction of frontal-striatal, particularly orbitofrontal-striatal, circuitry has been implicated in the pathophysiology of obsessive-compulsive disorder (OCD), characterized by obsessions, ritualistic behavior, anxiety, and specific cognitive impairments. In addition, neuropsychological studies in OCD have reported impairments in visuospatial tasks and executive functions, such as planning. OBJECTIVE: To determine whether dorsal prefrontal-striatal dysfunction mediates planning impairment in patients with OCD. DESIGN: A parametric self-paced pseudorandomized event-related functional magnetic resonance imaging version of the Tower of London task was used in 22 medication-free patients with OCD and 22 healthy control subjects. This paradigm, allowing flexible responding and post hoc classification of correct responses, was developed to compare groups likely to differ in performance. RESULTS: Behavioral results showed significant planning impairments in OCD patients compared with control subjects. During planning, decreased frontal-striatal responsiveness was found in OCD patients, mainly in dorsolateral prefrontal cortex and caudate nucleus. In addition, OCD patients showed increased, presumably compensatory, involvement of brain areas known to play a role in performance monitoring and short-term memory processing, such as anterior cingulate, ventrolateral prefrontal, and parahippocampal cortices. CONCLUSIONS: These findings support the hypothesis that decreased dorsal prefrontal-striatal responsiveness is associated with impaired planning capacity in OCD patients. Because the described frontal-striatal dysfunction in OCD is independent of state anxiety and disease symptom severity, we conclude that executive impairment is a core feature in OCD.

Disorder-specific neuroanatomical correlates of attentional bias in obsessive-compulsive disorder, panic disorder, and hypochondriasis.

CONTEXT: Attentional bias to disease-relevant emotional cues is considered to be pathogenetically relevant in anxiety disorders. OBJECTIVE: To investigate functional neural correlates and disease specificity of attentional bias across different anxiety disorders. DESIGN: A cognitive and emotional Stroop task, consisting of congruent and incongruent color words, obsessive-compulsive disorder (OCD)-related and panic-related negative words, and neutral words, was used in 3 patient groups and a control group during functional magnetic resonance imaging. SETTING: Academic outpatient department for anxiety disorders. PATIENTS AND PARTICIPANTS: Medication-free patients with OCD (n = 16), panic disorder (PD) (n = 15), and hypochondriasis (n = 13) and 19 controls. MAIN OUTCOME MEASURE: Voxel-wise analyses of cerebral blood flow changes for contrasts of interest (incongruent vs congruent color words, OCD-related vs neutral words, and panic-related vs neutral words) within and between groups. RESULTS: During incongruent vs congruent color naming, all patient groups recruited additional posterior brain regions relative to controls, but performance was impaired only in OCD. In OCD, color naming OCD-related, but not PD-related, words correlated with increased activation of frontal-striatal and temporal regions, although performance was unimpaired. In contrast, in PD, increased frontal-striatal involvement was found during color naming both OCD-related and panic-related words. In PD, color naming panic-related words was slowed and correlated with increased activation of the right amygdala and hippocampus. Patients with hypochondriasis showed a similar activation pattern to patients with PD. CONCLUSIONS: Our results support the hypothesis of increased distractibility for irrelevant information in patients with OCD, PD, and hypochondriasis associated with frontal-striatal and limbic involvement compared with controls. Although patients with OCD did not display an attentional bias in behavior relative to controls, there was a clear, specific neural response during color naming OCD-related words, involving mainly ventral brain regions. In contrast, generalized emotional interference effects were found in PD and hypochondriasis, involving ventral and widespread dorsal brain regions, reflecting not only unconscious emotional stimulus processing but also increased cognitive elaboration.

Circuit-Based Corticostriatal Homologies Between Rat and Primate.

BACKGROUND: Understanding the neural mechanisms of psychiatric disorders requires the use of rodent models; however, frontal-striatal homologies between rodents and primates are unclear. In contrast, within the striatum, the shell of the nucleus accumbens, the hippocampal projection zone, and the amygdala projection zone (referred to as the striatal emotion processing network [EPN]) are conserved across species. We used the relationship between the EPN and projections from the anterior cingulate cortex (ACC) and orbitofrontal cortex (OFC) to assess network similarities across rats and monkeys. METHODS: We first compared the location and extent of each major component of the EPN in rats and macaques. Next, we used anatomic cases with anterograde injections in ACC/OFC to determine the extent to which corticostriatal terminal fields overlapped with these components and with each other. RESULTS: The location and size of each component of the EPN were similar across species, containing projections primarily from infralimbic cortex in rats and area 25 in monkeys. Other ACC/OFC terminals overlapped extensively with infralimbic cortex/area 25 projections, supporting cross-species similarities in OFC topography. However, dorsal ACC had different connectivity profiles across species. These results were used to segment the monkey and rat striata according to ACC/OFC inputs. CONCLUSIONS: Based on connectivity with the EPN, and consistent with prior literature, the infralimbic cortex and area 25 are likely homologues. We also see evidence of OFC homologies. Along with segmenting the striatum and identifying striatal hubs of overlapping inputs, these results help to translate findings between rodent models and human pathology.

Compensatory fronto-parietal hyperactivation during set-shifting in unmedicated patients with Parkinson's disease.

Patients with Parkinson's disease (PD) often suffer from impairments in executive functions, such as mental rigidity, which can be measured as impaired set-shifting. Previous studies have shown that set-shifting deficits in patients with PD result from hypo-excitation of the caudate nucleus and lateral prefrontal cortices. The results of these studies may have been influenced by the inclusion of patients on dopaminergic medication, and by choosing set-shifting paradigms in which performance also depends on other cognitive mechanisms, such as matching-to-sample. To circumvent these potential confounding factors, we tested patients with PD that were not on dopamine replacement therapy, and we developed a new feedback-based paradigm to measure the cognitive construct set-shifting more accurately. In this case-control study, 18 patients with PD and 35 well-matched healthy controls performed the set-shifting task, while task-related neural activation was recorded using functional magnetic resonance imaging. Behaviourally, PD patients, compared with healthy controls, made more errors during repeat trials, but not set-shift trials. The patients, compared with controls, showed increased task-related activation of the bilateral inferior parietal cortex, and the right superior frontal gyrus, and decreased activation of the right ventrolateral prefrontal cortex during set-shift trials. Our findings suggest that, despite decreased task-related activation of the right ventrolateral prefrontal cortex, these early-stage unmedicated patients with PD do not yet suffer from set-shifting deficits due to compensatory hyperactivation in the inferior parietal cortex and the superior frontal gyrus.

The medial prefrontal cortex in the rat: evidence for a dorso-ventral distinction based upon functional and anatomical characteristics.

The prefrontal cortex in rats can be distinguished anatomically from other frontal cortical areas both in terms of cytoarchitectonic characteristics and neural connectivity, and it can be further subdivided into subterritories on the basis of such criteria. Functionally, the prefrontal cortex of rats has been implicated in working memory, attention, response initiation and management of autonomic control and emotion. In humans, dysfunction of prefrontal cortical areas with which the medial prefrontal cortex of the rat is most likely comparable is related to psychopathology including schizophrenia, sociopathy, obsessive-compulsive disorder, depression, and drug abuse. Recent literature points to the relevance of conducting a functional analysis of prefrontal subregions and supports the idea that the area of the medial prefrontal cortex in rats is characterized by its own functional heterogeneity, which may be related to neuroanatomical and neurochemical dissociations. The present review covers recent findings with the intent of correlating these distinct functional differences in the dorso-ventral axis of the rat medial prefrontal cortex with anatomical and neurochemical patterns.

Relationships of the Dendritic Arborizations of Ventral Striatomesencephalic Projection Neurons With Boundaries of Striatal Compartments. An In Vitro Intracellular Labelling Study in the Rat.

We studied the relationships of the dendrites of ventral striatomesencephalic projection neurons with the compartmental structure of the ventral striatum, as revealed by enkephalin immunohistochemistry. Lightly fixed slices were employed in which Lucifer yellow was intracellularly injected into neurons that were retrogradely labelled following Fast Blue injections in the ventral tegmental area. Double immunohistochemical staining was carried out using antisera to Lucifer yellow and Leu-enkephalin. Most of the 226 injected cells were located in the core region of the nucleus accumbens. All these neurons were of the small- to medium-sized spiny type. The dendritic arborizations of over 90% of the cells remained within the compartment in which the parent cell bodies resided. The dendrites of most of these neurons abutted the border of the compartment, whereas a smaller number of neurons had dendrites that were distant from any compartmental boundary. The dendrites of fewer than 10% of the neurons crossed the borders of compartments. Only a few cells were injected in the shell region of the nucleus accumbens. None of these neurons extended its dendrites into the core region of the nucleus or into the territory of the clusters of small cells which characterize the shell. The present results demonstrate that the dendrites of the great majority of ventral striatomesencephalic neurons comply with the boundaries of ventral striatal enkephalin compartments. Together with the results of previous studies showing that such compartments are selectively innervated by thalamic and cortical afferents, and have outputs to different areas in the ventral mesencephalon, the present data suggest the existence of discrete channels through the ventral striatum.