The purpose of the present investigation was to examine the topographical organization of efferent projections from the cytoarchitectonic divisions of the mPFC (the medial precentral, dorsal anterior cingulate and prelimbic cortices). We also sought to determine whether the efferents from different regions within the prelimbic division were organized topographically. Anterograde transport of Phaseolus vulgaris leucoagglutinin was used to examine the efferent projections from restricted injection sites within the mPFC. Major targets of the prelimbic area were found to include prefrontal, cingulate, and perirhinal cortical structures, the dorsomedial and ventral striatum, basal forebrain nuclei, basolateral amygdala, lateral hypothalamus, mediodorsal, midline and intralaminar thalamic nuclei, periaqueductal gray region, ventral midbrain tegmentum, laterodorsal tegmental nucleus, and raphe nuclei. Previously unreported projections of the prelimbic region were also observed, including efferents to the anterior olfactory nucleus, the piriform cortex, and the pedunculopontine tegmental-cuneiform region. A topographical organization governed the efferent projections from the prelimbic area, such that the position of terminal fields within target structures was determined by the rostrocaudal, dorsoventral, and mediolateral placement of the injection sites. Efferent projections from the medial precentral and dorsal anterior cingulate divisions (dorsomedial PFC) were organized in a similar topographical fashion and produced a pattern of anterograde labeling different from that seen with prelimbic injection sites. Target structures innervated primarily by the dorsomedial PFC included certain neocortical fields (the motor, somatosensory, and visual cortices), the dorsolateral striatum, superior colliculus, deep mesencephalic nucleus, and the pontine and medullary reticular formation. Previously unreported projections to the paraoculomotor central gray area and the mesencephalic trigeminal nucleus were observed following dorsomedial PFC injections. These results indicate that the efferent projections of the mPFC are topographically organized within and across the cytoarchitectonic divisions of the medial wall cortex. The significance of topographically organized and restricted projections of the rat mPFC is discussed in light of behavioral and physiological studies indicating functional heterogeneity of this region.

Topographical organization of the efferent projections of the medial prefrontal cortex in the rat: An anterograde tract-tracing study with Phaseolus vulgaris leucoagglutinin

The cingulate gyrus is a major part of the "anatomical limbic system" and, according to classic accounts, is involved in emotion. This view is oversimplified in light of recent clinical and experimental findings that cingulate cortex participates not only in emotion but also in sensory, motor, and cognitive processes. Anterior cingulate cortex, consisting of areas 25 and 24, has been implicated in visceromotor, skeletomotor, and endocrine outflow. These processes include responses to painful stimuli, maternal behavior, vocalization, and attention to action. Since all of these activities have an affective component, it is likely that connections with the amygdala are critical for them. In contrast, posterior cingulate cortex, consisting of areas 29, 30, 23, and 31, contains neurons that monitor eye movements and respond to sensory stimuli. Ablation studies suggest that this region is involved in spatial orientation and memory. It is likely that connections between posterior cingulate and parahippocampal cortices contribute to these processes. We conclude that there is a fundamental dichotomy between the functions of anterior and posterior cingulate cortices. The anterior cortex subserves primarily executive functions related to the emotional control of visceral, skeletal, and endocrine outflow. The posterior cortex subserves evaluative functions such as monitoring sensory events and the organism's own behavior in the service of spatial orientation and memory.

Functional Heterogeneity in Cingulate Cortex: The Anterior Executive and Posterior Evaluative Regions

Functional magnetic resonance imaging (FMRI) was used to identify candidate language processing areas in the intact human brain. Language was defined broadly to include both phonological and lexical-semantic functions and to exclude sensory, motor, and general executive functions. The language activation task required phonetic and semantic analysis of aurally presented words and was compared with a control task involving perceptual analysis of nonlinguistic sounds. Functional maps of the entire brain were obtained from 30 right-handed subjects. These maps were averaged in standard stereotaxic space to produce a robust "average activation map" that proved reliable in a split-half analysis. As predicted from classical models of language organization based on lesion data, cortical activation associated with language processing was strongly lateralized to the left cerebral hemisphere and involved a network of regions in the frontal, temporal, and parietal lobes. Less consistent with classical models were (1) the existence of left hemisphere temporoparietal language areas outside the traditional "Wernicke area," namely, in the middle temporal, inferior temporal, fusiform, and angular gyri; (2) extensive left prefrontal language areas outside the classical "Broca area"; and (3) clear participation of these left frontal areas in a task emphasizing "receptive" language functions. Although partly in conflict with the classical model of language localization, these findings are generally compatible with reported lesion data and provide additional support for ongoing efforts to refine and extend the classical model.

https://www.jneurosci.org/content/jneuro/17/1/353.full.pdf

Human Brain Language Areas Identified by Functional Magnetic Resonance Imaging

What is the amygdala

The medial prefrontal cortex (mPFC) has been associated with diverse functions including attentional processes, visceromotor activity, decision making, goal directed behavior, and working memory. Using retrograde tracing techniques, we examined, compared, and contrasted afferent projections to the four divisions of the mPFC in the rat: the medial (frontal) agranular (AGm), anterior cingulate (AC), prelimbic (PL), and infralimbic (IL) cortices. Each division of the mPFC receives a unique set of afferent projections. There is a shift dorsoventrally along the mPFC from predominantly sensorimotor input to the dorsal mPFC (AGm and dorsal AC) to primarily 'limbic' input to the ventral mPFC (PL and IL). The AGm and dorsal AC receive afferent projections from widespread areas of the cortex (and associated thalamic nuclei) representing all sensory modalities. This information is presumably integrated at, and utilized by, the dorsal mPFC in goal directed actions. In contrast with the dorsal mPFC, the ventral mPFC receives significantly less cortical input overall and afferents from limbic as opposed to sensorimotor regions of cortex. The main sources of afferent projections to PL/IL are from the orbitomedial prefrontal, agranular insular, perirhinal and entorhinal cortices, the hippocampus, the claustrum, the medial basal forebrain, the basal nuclei of amygdala, the midline thalamus and monoaminergic nuclei of the brainstem. With a few exceptions, there are few projections from the hypothalamus to the dorsal or ventral mPFC. Accordingly, subcortical limbic information mainly reaches the mPFC via the midline thalamus and basal nuclei of amygdala. As discussed herein, based on patterns of afferent (as well as efferent) projections, PL is positioned to serve a direct role in cognitive functions homologous to dorsolateral PFC of primates, whereas IL appears to represent a visceromotor center homologous to the orbitomedial PFC of primates.

Anatomical analysis of afferent projections to the medial prefrontal cortex in the rat

The topography of the mesencephalic and pontine projections from the cingulate cortex of the rat

The topographic relationships between anterior thalamic neurons and their terminal projection fields in the retrosplenial cortex of the rat were characterized by experiments with the fluorescent dye retrograde labeling technique. The results demonstrate that the anterodorsal (DAD) and anteroventral (AV) nuclei project heavily to retrosplenial granular cortex (Rg) and to a lesser extent to retrosplenial agranular cortex (Rag). In contrast, the anteromedial (AM) and lateral dorsal (LD) nuclei project heavily to Rag and more lightly to Rg. Irrespective of terminal field in Rg or Rag, the neuronal cell bodies in AD and AV are organized topographically so that the neurons in the caudal part of each nucleus project to rostral retrosplenial cortex and the neurons in the rostral portion of each nucleus project to the caudal retrosplenial cortex. Further, the ventromedial AD and AV neurons project to rostral retrosplenial cortex, whereas dorsolateral neurons in both nuclei project to caudal retrosplenial cortex. LD neurons display a different topographic organization. The neurons in the medioventral part of LD project primarily to the rostral retrosplenial cortex, and the neurons in lateral LD project to the caudal retrosplenial cortex. This latter projection to the caudal retrosplenial cortex is also contributed to by neurons residing in the mediodorsal part of caudal LD. The neurons in AM that project to the retrosplenial cortex display less segregation than the AV, AD, or LD neurons. In all experiments, a number of neurons in the dorsal ventro-anterolateral nucleus were labeled by retrosplenial injections. The largest number of cells in this nucleus were labeled after Rag injections, and these were topographically organized such that the neurons projecting to the rostral Rag were located immediately deep to the internal medullary lamina, and the neurons projecting to the caudal Rag were more ventrally located. Very few thalamic neurons have axon collaterals to different areas of the retrosplenial cortex as shown by double labeling experiments. Together, these results demonstrate a highly organized thalamic projection to the retrosplenial cortex.

Thalamic projections to retrosplenial cortex in the rat

The fluorescent dye, retrograde labeling technique was used to determine the extent of the projection from the basolateral nucleus of the amygdala to the neocortex in the rat. Each rat received a single cortical injection of fast blue, and in one-half of the animals, a subsequent injection of nuclear yellow was placed in a different cortical region. An analysis of the results demonstrates that the projection to the midline cortex arises in the medial neurons within the caudal two-thirds of the basolateral nucleus. This projection is directed to the anterior cingulate cortex, but not to the posterior cingulate cortex. The primary motor cortex receives a basolateral amygdala projection which originates from neurons in two areas, (1) the medial part of the anterior one-third of the nucleus and (2) the center (in the lateral to medial axis) portion of the posterior two-thirds of the nucleus. The latter neurons are situated lateral to the neurons projecting to the cingulate cortex. Somatosensory cortex injections label many fewer basolateral nucleus neurons than do motor cortex injections, but these neurons are located in a position similar to that of those labeled by motor cortex injections. Finally the gustatory cortex, which lies just dorsal to the rhinal sulcus, receives a basolateral projection from neurons in the lateroventral one-half of the basolateral nucleus. These results demonstrate that the basolateral nucleus gives rise to a rather widespread and topographically organized projection to the anterior half of the neocortex of the rat.

The cortical projection of the basolateral amygdaloid nucleus in the rat: a retrograde fluorescent dye study.

The morphology and connections of the indusium griseum (IG) and anterior hippocampal continuation (AHC) suggest that this cortex contains analogues to several portions of the hippocampal formation. Whereas the outer neuronal layer of this cortex is made up of cells which are similar in structure to the neurons of the granule cell layer of the dentate gyrus, the three successively deeper layers contain morphological analogues to the neurons of the dentate hilus, Ammon's horn, and the subiculum, respectively. The neurons within each of these four layers of the AHC and IG have afferent and efferent connections which are quite similar to the connections of their hippocampal counterparts. Thus, the granule cells of the IG and AHC receive laminar inputs from the entorhinal cortex, the IG-AHC itself, and the supramammillary region. Each of these three classes of inputs ends at successively more proximal positions on the dendritic tree of these granule cells. Other inputs to this region include those from the septal nuclei and the olfactory bulb. The deeper layers of the IG and AHC receive several inputs, including those from the thalamic and septal nuclei and the entorhinal cortex. The efferent cell bodies of the IG and AHC are segregated in such a way that the granule cells appear to give rise to only short connections, while the hilar cells project to the granule cells, the intermediate pyramidal neurons project to other portions of the IG and AHC and to the olfactory bulb, and the deep pyramidal neurons project to the diencephalon. These results demonstrate that the IG-AHC is a continuation of the hippocampal formation.

The indusium griseum and anterior hippocampal continuation in the rat

Neuroinflammation is pathological evidence of Alzheimer's disease (AD) that likely starts as a host defense response to the damaging effects of the β-amyloid (Aβ) deposits in the brain. The activation of microglia may promote the neurodegenerative process through the release of proinflammatory cytokines, such as interleukin-1β (IL-1β) and tumor necrosis factor-α (TNFα), which may lead to neuronal damage and eventual death. Aged garlic extract (AGE) has been reported to have multiple biological activities, including anti-inflammatory effects. Therefore, the objective of this study was to investigate the effect of AGE on Aβ (1-42)-induced cognitive dysfunction and neuroinflammation. Adult male Wistar rats were given AGE (125, 250, and 500 mg/kg BW, body weight), orally administered, daily for 56 days. They were then injected with 1 μL of aggregated Aβ (1-42) into the lateral ventricles; bilaterally. Seven days later, their recognition memory was evaluated using a novel object recognition (NOR) test. Then the rats were sacrificed to investigate the alteration of microglia cells, IL-1β and TNFα in the cerebral cortex and hippocampus. The results indicated that AGE at doses of 250 and 500 mg/kg BW significantly improved short-term recognition memory in cognitively impaired rats. In addition, AGE significantly minimized the inflammatory response by reducing the activation of microglia and IL-1β to the levels found in the control, which is similar to the results found in Celebrex-treated rats. In conclusion, AGE may be useful for improving the short-term recognition memory and relieve the neuroinflammation in Aβ-induced rats.

Kittisak Sripanidkulchai

Papers

The topography of the mesencephalic and pontine projections from the cingulate cortex of the rat

Thalamic projections to retrosplenial cortex in the rat

The cortical projection of the basolateral amygdaloid nucleus in the rat: a retrograde fluorescent dye study.

The indusium griseum and anterior hippocampal continuation in the rat

Neuroprotective Effects of Aged Garlic Extract on Cognitive Dysfunction and Neuroinflammation Induced by β-Amyloid in Rats.