The present study examines subcortical connections of paraventricular thalamic nucleus (Pa) following small anterograde and retrograde tracer injections in cynomolgus monkeys (Macaca fascicularis). An anterograde tracer injection into the dorsal midline thalamus revealed strong projections to the accumbens nucleus, basal amygdala, lateral septum, and hypothalamus. Retrograde tracer injections into these areas labeled neurons specifically in Pa. Following a retrograde tracer injection into Pa, labeled neurons were found in the hypothalamus, dorsal raphe, and periaqueductal gray. Pa contained a remarkably high density of axons and axonal varicosities immunoreactive for serotonin (5-HT) and orexin/hypocretin (ORX), as well as a moderate density of fibers immunoreactive for corticotropin-releasing hormone (CRH). A retrograde tracer injection into Pa combined with immunohistochemistry demonstrated that ORX and 5-HT axons originate from neurons in the hypothalamus and midbrain. Pa-projecting neurons were localized in the same nuclei of the hypothalamus, amygdala, and midbrain as CRH neurons, although no double labeling was found. The connections of Pa and its innervation by 5-HT, ORX, and CRH suggest that it may relay stress signals between the midbrain and hypothalamus with the accumbens nucleus, basal amygdala, and subgenual cortex as part of a circuit that manages stress and possibly stress-related psychopathologies.

Although the perirhinal and parahippocampal cortices have been shown to be critically involved in memory processing, the boundaries and extent of these areas have been controversial. To produce a more objective and reproducible description, the architectonic boundaries and structure of the perirhinal (areas 35 and 36) and parahippocampal (areas TF and TH) cortices were analyzed in three macaque species, with four different staining methods [Nissl and immunohistochemistry for parvalbumin, nonphosphorylated neurofilaments (with SMI-32), and the m2 muscarinic acetylcholine receptor]. We further correlated the architectonic boundary of the parahippocampal cortex with connections to and from different subregions of anterior area TE and with previously published connections with the prefrontal cortex and temporal pole (Kondo et al. [2005] J. Comp. Neurol. 493:479-509). Together, these data provided a clear delineation of the perirhinal and parahippocampal areas, although it differs from previous descriptions. In particular, we did not extend the perirhinal cortex into the temporal pole, and the lateral boundaries of areas 36 and TF with area TE were placed more medially than in other studies. The lateral boundary of area TF in Macaca fuscata was located more laterally than in Macaca fascicularis or Macaca mulatta, although there was no difference in architectonic structure. We recognized a caudal, granular part of the parahippocampal cortex that we termed "area TFO." This area closely resembles the laterally adjacent area TE and the caudally adjacent area V4 but is clearly different from the more rostral area TF. These areas are likely to have distinct functions.

To determine the frequency and possible cognitive effect of histological Alzheimer's disease (AD) in autopsied older nondemented individuals.

The origin and termination of axonal connections between the orbital and medial prefrontal cortex (OMPFC) and the temporal, insular, and opercular cortex have been analyzed with anterograde and retrograde axonal tracers, injected in the OMPFC or temporal cortex. The results show that there are two distinct, complementary, and reciprocal neural systems, related to the previously defined "orbital" and "medial" prefrontal networks. The orbital prefrontal network, which includes areas in the central and lateral part of the orbital cortex, is connected with vision-related areas in the inferior temporal cortex (especially area TEav) and the fundus and ventral bank of the superior temporal sulcus (STSf/v), and with somatic sensory-related areas in the frontal operculum (OPf) and dysgranular insular area (Id). No connections were found between the orbital network and auditory areas. The orbital network is also connected with taste and olfactory cortical areas and the perirhinal cortex and appears to be involved in assessment of sensory objects, especially food. The medial prefrontal network includes areas on the medial surface of the frontal lobe, medial orbital areas, and two caudolateral orbital areas. It is connected with the rostral superior temporal gyrus (STGr) and the dorsal bank of the superior temporal sulcus (STSd). This region is rostral to the auditory parabelt areas, and there are only relatively light connections between the auditory areas and the medial network. This system, which is also connected with the entorhinal, parahippocampal, and cingulate/retrosplenial cortex, may be involved in emotion and other self-referential processes.

MRI-based reports of both abnormally increased and decreased amygdala volume in bipolar disorder (BD) have surfaced in the literature. Two major methodological weaknesses characterizing extant studies are treatment with medication and inaccurate segmentation of the amygdala due to limitations in spatial and tissue contrast resolution. Here, we acquired high-resolution images (voxel size=0.55 x 0.55 x 0.60 mm) using a GE 3T MRI scanner, and a pulse sequence optimized for tissue contrast resolution. The amygdala was manually segmented by one rater blind to diagnosis, using coronal images. Eighteen unmedicated (mean medication-free period 11+/-10 months) BD subjects were age and gender matched with 18 healthy controls, and 17 medicated (lithium or divalproex) subjects were matched to 17 different controls. The unmedicated BD patients displayed smaller left and right amygdala volumes than their matched control group (p<0.01). Conversely, the BD subjects undergoing medication treatment showed a trend towards greater amygdala volumes than their matched HC sample (p=0.051). Right and left amygdala volumes were larger (p<0.05) or trended larger, respectively, in the medicated BD sample compared with the unmedicated BD sample. The two control groups did not differ from each other in either left or right amygdala volume. BD patients treated with lithium have displayed increased gray matter volume of the cortex and hippocampus relative to untreated BD subjects in previous studies. Here we extend these results to the amygdala. We raise the possibility that neuroplastic changes in the amygdala associated with BD are moderated by some mood stabilizing medications.

In this era of complete genomes, our knowledge of neuroanatomical circuitry remains surprisingly sparse. Such knowledge is critical, however, for both basic and clinical research into brain function. Here we advocate for a concerted effort to fill this gap, through systematic, experimental mapping of neural circuits at a mesoscopic scale of resolution suitable for comprehensive, brainwide coverage, using injections of tracers or viral vectors. We detail the scientific and medical rationale and briefly review existing knowledge and experimental techniques. We define a set of desiderata, including brainwide coverage; validated and extensible experimental techniques suitable for standardization and automation; centralized, open-access data repository; compatibility with existing resources; and tractability with current informatics technology. We discuss a hypothetical but tractable plan for mouse, additional efforts for the macaque, and technique development for human. We estimate that the mouse connectivity project could be completed within five years with a comparatively modest budget.