Medial Limbic Cortex Research Articles

Dreaming as a story-telling instinct

Dreams create new stories out of nothing. Although dreams contain themes, concerns, dream figures, objects, etc. that correspond closely to waking life, these are only story elements. The story itself weaves these mnemonic items together in a manner far more novel than a simple assemblage or collage, producing an experience having a life-like timeframe and life-like (if often bizarre and impossible) causality (Pace-Schott, 2007; Hobson, 2009). It is as if one is immersed in another “reality” entirely of one’s own non-volitional, making (see Rechtschaffen, 1978). Given this phenomenology, it’s not difficult to see why some indigenous animist societies believe dreams represent a separate world parallel with waking life (Nielsen, 1991). But neuroscience offers some other explanations. Recent speculations have focused on the brain’s “default network” as a possible neural substrate of dreaming (Pace-Schott, 2007, 2011a,b; Nir and Tononi, 2010; Wamsley and Stickgold, 2010; Domhoff, 2011). The default network consists of regions that, in the absence of exteroceptive attention or narrowly focused mental effort, support self-directed concerns, immersion in one’s inner life (e.g., daydreaming) or imagining the inner life of others (Theory of Mind) (Buckner et al., 2008; Andrews-Hanna, 2012; Buckner, 2012). Most importantly for the current topic, the default network also simulates future scenarios and re-creates past ones drawing upon material in episodic, autobiographical, and semantic memory (Schacter et al., 2007; Schacter, 2012). Here I will suggest that such constructive activities of the brain represent a “hardwired” tendency to represent reality in the form of narrative—a “story-telling” instinct or module. The default network was originally identified using positron emission tomography (PET) as those regions showing task-induced deactivation (Gusnard et al., 2001; Raichle et al., 2001). Subsequently, it was discovered that temporal synchrony of low frequency (0.01–0.1 Hz) spontaneous fluctuations of the blood-oxygen dependent (BOLD) signal of fMRI identifies both anatomical and functional connectivity among regions of the default network (Fox and Raichle, 2007; Greicius et al., 2008). This network consists of (1) medial parietal areas: posterior cingulate (pCC) and retrosplenial (Rsp) cortices; (2) posterior-lateral areas: inferior parietal lobule (IPL), temporoparietal junction (TPJ), lateral temporal cortex (LTC), temporal poles (TP); (3) medial temporal regions: hippocampal formation (HF), parahippocampal cortex (PHC); and (4) medial prefrontal areas: ventromedial (vmPFC) and dorsomedial (dmPFC) prefrontal cortices (Buckner et al., 2008; Spreng et al., 2009; Andrews-Hanna, 2012). Resting state functional connectivity analyses of BOLD oscillations in waking have identified two default-network subsystems each of which fluctuates synchronously with central nodes in the pCC and anterior medial PFC (amPFC) but not with each other (Buckner et al., 2008; Andrews-Hanna et al., 2010; AndrewsHanna, 2012). The dorsomedial prefrontal subsystem includes the dmPFC, LTC, TPJ, and TP whereas the medial temporal lobe subsystem includes the HF, PHC, Rsp, IPL, and vmPFC. The dorsomedial prefrontal subsystem selectively activates during experimental tasks involving reflection on one’s own mental state and that of others as well as other forms of social cognition (Andrews-Hanna et al., 2010; Mar, 2011; Andrews-Hanna, 2012). In contrast, the medial temporal lobe subsystem is selectively activated by retrieval of episodic and autobiographical memories as well as by imagination of future scenarios and concerns (Schacter et al., 2007; AndrewsHanna et al., 2010; Andrews-Hanna, 2012; Schacter, 2012). The central nodes activate along with most tasks that recruit one or the other subsystem (Andrews-Hanna, 2012). Synchrony of BOLD fluctuations among components of the default network persists into light (Drummond et al., 2005; Horovitz et al., 2008; Larson-Prior et al., 2009) and Stage 2 (Laufs et al., 2007) NREM sleep. However, in slowwave sleep (SWS), frontal regions may uncouple from the rest of the default network (Horovitz et al., 2009; Samann et al., 2011, but see Koike et al., 2011). In the one study examining REM, unlike both waking and NREM, there appeared a lack of connectivity between the dorsomedial prefrontal subsystem and the posterior central node of the default network in the pCC (Koike et al., 2011). Koike et al. speculate that this disconnection contributes to the illogic and bizarreness of dream cognition, as has also been suggested for loss of antero-posterior EEG synchrony in the fast, gamma (>30 Hz) frequencies during REM (Corsi-Cabrera et al., 2003, 2008). Earlier PET and fMRI activational studies of sleep also showed distinctly different activity in medial limbic versus lateral association cortex during REM sleep. After sleep onset during NREM, widespread cortical and subcortical areas become less active (Braun et al., 1997; Maquet et al., 1997; Nofzinger et al., 2002; Kaufmann et al., 2006). However, with the onset of REM sleep, midline limbic regions of the frontal cortex and subcortex reactivate to levels equaling and sometimes exceeding those of waking, whereas lateral and posterior-medial cortical areas remain in a NREM-like deactivated state (Maquet et al., 1996, 2005; Braun et al., 1997,

Early Postnatal Migration and Development of Layer II Pyramidal Neurons in the Rodent Cingulate/Retrosplenial Cortex

The cingulate and retrosplenial regions are major components of the dorsomedial (dm) limbic cortex and have been implicated in a range of cognitive functions such as emotion, attention, and spatial memory. While the structure and connectivity of these cortices are well characterized, little is known about their development. Notably, the timing and mode of migration that govern the appropriate positioning of late-born neurons remain unknown. Here, we analyzed migratory events during the early postnatal period from ventricular/subventricular zone (VZ/SVZ) to the cerebral cortex by transducing neuronal precursors in the VZ/SVZ of newborn rats/mice with Tomato/green fluorescent protein-encoding lentivectors. We have identified a pool of postmitotic pyramidal precursors in the dm part of the neonatal VZ/SVZ that migrate into the medial limbic cortex during the first postnatal week. Time-lapse imaging demonstrates that these cells migrate on radial glial fibers by locomotion and display morphological and behavioral changes as they travel through the white matter and enter into the cortical gray matter. In the granular retrosplenial cortex, these cells give rise to a Satb2+ pyramidal subtype and develop dendritic bundles in layer I. Our observations provide the first insight into the patterns and dynamics of cell migration into the medial limbic cortex.

Frontal and posterior sources of event-related potentials in semantic comprehension

An important question in brain and language research is how activity in multiple brain networks is coordinated over time during semantic comprehension. To address this question, we applied spatiotemporal source analysis to event-related potentials (ERPs) recorded as subjects read words that were meaningful or incongruous in the context of a sentence (N400 paradigm). The incongruous word was placed either early in the sentence or at the end. Source analysis showed activity in language areas of the left hemisphere, right temporal cortex and medial limbic cortex. The initial detection of semantic incongruity (∼250 ms) engaged the left prefrontal cortex and left anterior cingulate. In the critical (300–500 ms) interval, regional sources in left and right lateral prefrontal cortex, right temporal cortex, and both anterior and posterior cingulate were responsive to the semantic manipulation. Left hemisphere activity preceded right hemisphere activity, and semantic effects in frontal regions began earlier and were more sustained than the transient effects within posterior cortical regions. Findings are discussed with respect to recent theories of corticothalamic and corticolimbic networks in attention and semantic processing.

Frontal and posterior sources of event-related potentials in semantic comprehension

An important question in brain and language research is how activity in multiple brain networks is coordinated over time during semantic comprehension. To address this question, we applied spatiotemporal source analysis to event-related potentials (ERPs) recorded as subjects read words that were meaningful or incongruous in the context of a sentence (N400 paradigm). The incongruous word was placed either early in the sentence or at the end. Source analysis showed activity in language areas of the left hemisphere, right temporal cortex and medial limbic cortex. The initial detection of semantic incongruity (∼250 ms) engaged the left prefrontal cortex and left anterior cingulate. In the critical (300–500 ms) interval, regional sources in left and right lateral prefrontal cortex, right temporal cortex, and both anterior and posterior cingulate were responsive to the semantic manipulation. Left hemisphere activity preceded right hemisphere activity, and semantic effects in frontal regions began earlier and were more sustained than the transient effects within posterior cortical regions. Findings are discussed with respect to recent theories of corticothalamic and corticolimbic networks in attention and semantic processing.

Topographic organization of connections between the hypothalamus and prefrontal cortex in the rhesus monkey.

Prefrontal cortices have been implicated in autonomic function, but their role in this activity is not well understood. Orbital and medial prefrontal cortices receive input from cortical and subcortical structures associated with emotions. Thus, the prefrontal cortex may be an essential link for autonomic responses driven by emotions. Classic studies have demonstrated the existence of projections between prefrontal cortex and the hypothalamus, a central autonomic structure, but the topographic organization of these connections in the monkey has not been clearly established. We investigated the organization of bidirectional connections between these areas in the rhesus monkey by using tracer injections in orbital, medial, and lateral prefrontal areas. All prefrontal areas investigated received projections from the hypothalamus, originating mainly in the posterior hypothalamus. Differences in the topography of hypothalamic projection neurons were related to both the location and type of the target cortical area. Injections in lateral eulaminate prefrontal areas primarily labeled neurons in the posterior hypothalamus that were equally distributed in the lateral and medial hypothalamus. In contrast, injections in orbitofrontal and medial limbic cortices labeled neurons in the anterior and tuberal regions of the hypothalamus and in the posterior region. Projection neurons targeting orbital limbic cortices were more prevalent in the lateral part of the hypothalamus, whereas those targeting medial limbic cortices were more prevalent in the medial hypothalamus. In comparison to the ascending projections, descending projections from prefrontal cortex to the hypothalamus were highly specific, originating mostly from orbital and medial prefrontal cortices. The ascending and descending connections overlapped in the hypothalamus in areas that have autonomic functions. These results suggest that specific orbitofrontal and medial prefrontal areas exert a direct influence on the hypothalamus and may be important for the autonomic responses evoked by complex emotional situations.

Emx1 and Emx2 functions in development of dorsal telencephalon.

The genes Emx1 and Emx2 are mouse cognates of a Drosophila head gap gene, empty spiracles, and their expression patterns have suggested their involvement in regional patterning of the forebrain. To define their functions we introduced mutations into these loci. The newborn Emx2 mutants displayed defects in archipallium structures that are believed to play essential roles in learning, memory and behavior: the dentate gyrus was missing, and the hippocampus and medial limbic cortex were greatly reduced in size. In contrast, defects were subtle in adult Emx1 mutant brain. In the early developing Emx2 mutant forebrain, the evagination of cerebral hemispheres was reduced and the roof between the hemispheres was expanded, suggesting the lateral shift of its boundary. Defects were not apparent, however, in the region where Emx1 expression overlaps that of Emx2, nor was any defect found in the early embryonic forebrain caused by mutation of the Emx1 gene, of which expression principally occurs within the Emx2-positive region. Emx2 most likely delineates the palliochoroidal boundary in the absence of Emx1 expression during early dorsal forebrain patterning. In the more lateral region of telencephalon, Emx2-deficiency may be compensated for by Emx1 and vice versa. Phenotypes of newborn brains also suggest that these genes function in neurogenesis corresponding to their later expressions.

Dentate gyrus formation requires Emx2.

Emx 1 and 2 are the murine homologues of the Drosophila empty spiracles gene and based on their expression pattern may be involved in the regional specification of the mammalian forebrain. During early embryogenesis, Emx2 is expressed in the presumptive cerebral cortex and olfactory bulbs and later, in the hippocampus proper and dentate gyrus. The latter are involved in memory processes. To understand the role of Emx2 in vivo, we have mutated the gene in mice. Homozygous embryos die postnatally because of severe urogenital alterations. These mice present cerebral hemispheres with a reduced size and exhibit specific morphological alterations in allocortical structures of the medial wall of the brain. The dentate gyrus is missing and the hippocampus proper is reduced. The medial limbic cortex is also severely shortened. The development of the dentate gyrus is affected at the onset of its formation with defects in the neuroepithelium from which it originates. These findings demonstrate that Emx2 is required for the development of several forebrain structures.

Cellular Localization of NGF and NT-3 mRNAs in Postnatal Rat Forebrain

The presence of transiently elevated levels of mRNA for nerve growth factor (NGF) and neurotrophin-3 (NT-3) in postnatal development of several brain areas suggests that these factors may be expressed by a greater number of cell types in the immature than in the adult brain. To evaluate this possibility, in situ hybridization was used to determine the cellular localization of NGF mRNA and NT-3 mRNA in hippocampus, cingulate cortex, posterolateral neocortex, thalamus, and cerebellum of post natal rat. In areas expressing both neurotrophins (i.e., hippocampus, cingulate cortex, and anteroventral thalamus), NT-3 mRNA was detected at earlier ages than NGF mRNA. Patterns of hybridization in hippocampus and cerebellum indicate that NT-3 is expressed by neurons soon after leaving the mitotic cycle whereas NGF expression is a feature of more mature neurons. The exception to this pattern was NGF expression in the lateral geniculate nuclei which was present by Postnatal Day 1 and retained in the adult. Both neurotrophins were transiently expressed in several brain areas. The loss of expression with age was most striking in thalamus with transient expression of NT-3 mRNA by the majority of dorsal thalamic relay nuclei and of NGF mRNA by fewer nuclei including the posterior, anteroventral, ventrolateral, and ventromedial nuclei. NT-3 expression also was transient in caudal cingulate/retrosplenial cortex, hippocampal CA3 stratum pyramidale, and the granule cells of archicerebellum. In early postnatal cingulate and retrosplenial cortices there were reciprocal rostrocaudal gradients of NGF and NT-3 expression. These results suggest both distinct and overlapping functions for NT-3 and NGF in early developmental processes including involvement of NT-3 in cerebellar development and of NGF in the development and maintenance of visual afferents to thalamus. Patterns of neurotrophin expression in medial limbic cortex may establish trophic gradients which influence the topography of thalamic innervation.

Diverse thalamic projections to the prefrontal cortex in the rhesus monkey

We studied the sources of thalamic projections to prefrontal areas of nine rhesus monkeys with the aid of retrograde tracers (horseradish peroxidase or fluorescent dyes). Our goal was to determine the proportion of labeled neurons contributing to this projection system by the mediodorsal (MD) nucleus compared to those distributed in other thalamic nuclei, and to investigate the relationship of thalamic projections to specific architectonic areas of the prefrontal cortex. We selected areas for study within both the basoventral (areas 11, 12, and ventral 46) and the mediodorsal (areas 32, 14, 46, and 8) prefrontal sectors. This choice was based on our previous studies, which indicate differences in cortical projections to these two distinct architectonic sectors (Barbas, '88; Barbas and Pandya, '89). In addition, for each sector we included areas with different architectonic profiles, which is also relevant to the connectional patterns of the prefrontal cortices. The results showed that MD included a clear majority (over 80%) of all thalamic neurons directed to some prefrontal cortices (areas 11, 46, and 8); it contributed just over half to some others (areas 12 and 32), and less than a third to area 14. Clusters of neurons directed to basoventral and mediodorsal prefrontal areas were largely segregated within MD: the former were found ventrally, the latter dorsally. However, the most striking findings establish a relationship between thalamic origin and laminar definition of the prefrontal target areas. Most thalamic neurons directed to lateral prefrontal cortices, which are characterized by a high degree of laminar definition (areas 46 and 8), originated in the parvicellular and multiform subdivisions of MD, and only a few were found in other nuclei. In contrast, orbital and medial cortices, which have a low degree of laminar differentiation, were targeted by the magnocellular subdivision of MD and by numerous other limbic thalamic nuclei, including the midline and the anterior. Thus topographic specificity in the origin of thalamic projections increased as the laminar definition of the target area increased. Moreover, the rostrocaudal distribution of labeled neurons in MD and the medial pulvinar also differed depending on the degree of the laminar definition of the prefrontal target areas. The rostral parts of MD and the medial pulvinar projected to the eulaminate lateral prefrontal cortices, whereas their caudal parts projected to orbital and medial limbic cortices. Selective destruction of caudal MD is known to disrupt mnemonic processes in both humans and monkeys, suggesting that this thalamic-limbic prefrontal loop may constitute an important pathway for memory.

Projections from the amygdala to basoventral and mediodorsal prefrontal regions in the rhesus monkey

The sources of ipsilateral projections from the amygdala to basoventral and mediodorsal prefrontal cortices were studied with retrograde tracers (horseradish peroxidase or fluorescent dyes) in 13 rhesus monkeys. The basoventral regions injected with tracers included the orbital periallocortex and proisocortex, orbital areas 13, 11, and 12, lateral area 12, and ventral area 46. The mediodorsal regions included portions of medial areas 25, 32, 14, and dorsal area 8. The above sites represent areas within two architectonic series of cortices referred to as basoventral or mediodorsal on the basis of their anatomic location. Each series consists of areas that show a gradual increase in the number of layers and their delineation in a direction from the caudal orbital and medial limbic cortices, which have an incipient laminar organization, towards the eulaminated periarcuate cortices (Barbas and Pandya, J. Comp. Neurol. 286: 353-375, '89). Labeled neurons projecting to the prefrontal cortex were found in the basolateral, basomedial (also known as accessory basal), lateral, and ventral cortical nuclei, and in the anterior amygdaloid and amygdalopiriform areas. The distribution of labeled neurons differed both quantitatively and qualitatively depending on whether the injection sites were in basoventral or mediodorsal prefrontal cortices. Cases with caudal orbital injections had the most labeled neurons in the amygdala, followed by cases with injections in cortices situated medioventrally. The latter received a high proportion of their amygdaloid projections from the basomedial nucleus. The lateral amygdaloid nucleus sent a robust projection to the least architectonically differentiated orbital periallocortex, and a weaker projection to the adjoining orbital proisocortical regions, but did not appear to project to either medial proisocortical sites or to the more differentiated ventrolateral or dorsolateral prefrontal cortices. In addition, there were topographical differences in the origin of projections from one amygdaloid nucleus directed to various prefrontal cortices. These differences were correlated either with the destination of the axons of afferent amygdaloid neurons to basoventral or to mediodorsal prefrontal cortices and/or with their projection to areas with varying degrees of laminar organization within the basoventral or mediodorsal sector. The clearest topography was observed for projections originating in the basolateral nucleus.(ABSTRACT TRUNCATED AT 400 WORDS)

Neurogenetic patterns in the medial limbic cortex of the rat related to anatomical connections with the thalamus and striatum

[ 3H]Thymidine autoradiography was used to investigate neurogenesis in all areas of the limbic cortex in the medial wall of the hemisphere. The experimental animals were the offspring of pregnant females injected with [ 3H]thymidine on 2 consecutive days: Embryonic Day (E)13–E14, E14–E15, …E21–E22, respectively. On Postnatal Day (P)60, the proportion of neurons originating during 24-h periods were quantified at nine anteroposterior levels. Three types of neurogenetic gradients are found. (i) Deep cells are older than superficial cells: layer VI is generated mainly on E15–E16, layer V on E16–E18, and layers IV-II on E18–E20. (ii) There is a ventral/older to dorsal/younger gradient between the dorsal peduncular, infralimbic, and anterior cingulate areas rostral to the genu of the corpus callosum. A ventral/older to dorsal/younger gradient is also found between superficial cells (layers II–IV) in anterior cingulate (CG3/CG1), posterior cingulate (CG2/CG1), and retrosplenial areas (RSG/RSA). (iii) An anterior/older to posterior/younger gradient is found between areas throughout the medial limbic cortex. Some of these neurogenetic patterns correlate with anatomical interconnections between the supracallosal medial limbic cortex (posterior cingulate and retrosplenial areas) and the anteroventral/anteromedial thalamic nuclei: older thalamic cells have longer axons that terminate in cortical areas containing younger cells, while younger thalamic cells have shorter axons that terminate in cortical areas containing older cells. Projections from the medial limbic cortex to the striatum also correlate with neurogenetic gradients: older cortical source cells in the infralimbic area project to the older striatal cells in the enkephalin-rich patches, while younger cortical source cells in the cingulate areas project to younger striatal cells in the surrounding matrix.

Development of the lateral and medial limbic cortices in the rat in relation to cortical phylogeny

[ 3H]Thymidine autoradiography was used to investigate neurogenesis of the lateral limbic cortex and morphogenesis of the medial and lateral limbic cortices in adult and embryonic rat brains. Ontogenetic patterns in the limbic cortex are unique because some neurogenetic gradients are linked to those in neocortex, others are linked to those in paleocortex. These findings are related to hypotheses of cortical phylogeny. The experimental animals used for neurogenesis were the off-spring of pregnant females injected with [ 3H]thymidine on 2 consecutive days: Embryonic Day (E)13–E14, E14–E15, …E21–E22, respectively. On Postnatal Day (P)60, the proportion of neurons originating during 24-h periods were quantified at nine anteroposterior levels and one sagittal level. Similar to neocortex, deep cells are generated earlier than superficial cells throughout the lateral limbic cortex: layer VI mainly on E14–15, layer V on E15–E16, and layers IV-II on E16–E18. There is a ventral/older to dorsal/younger neurogenetic gradient between the ventral agranular insular, dorsal agranular insular, and gustatory cortical areas and between ventral and dorsal orbital areas beneath the frontal pole. Similar to paleocortex below the rhinal sulcus, limbic cortex in the rhinal sulcus has a “sandwich” gradient: the older posterior agranular insular area is sandwiched by anterior and posterior younger areas (ventral agranular insular and perirhinal). To study morphogenesis, pregnant females were given single injections of [ 3H]thymidine during gestation and embryos were removed in successive 24-h intervals (sequential-survival). Neurogenesis finishes first in ventral limbic areas, later in dorsal limbic areas, and latest in neocortical areas. The cortical plate in the region of the medial and lateral limbic cortices does not have a separate subplate layer as is found in the region of the neocortex. Instead, layer VI in the limbic cortices has unusually older cells that are generated simultaneously with subplate cells.

Anatomic organization of basoventral and mediodorsal visual recipient prefrontal regions in the rhesus monkey.

The sources of ipsilateral cortical afferent projections to basoventral and mediodorsal prefrontal cortices that receive some visual input were studied with retrograde tracers (horseradish peroxidase or fluorescent dyes) in eight rhesus monkeys. The basoventral regions injected with tracers included basal (orbital) areas 11 and 12, lateral area 12, and ventral area 46. The mediodorsal regions included portions of medial area 32 and the caudal part of dorsal area 8. These sites represent areas within basoventral and mediodorsal prefrontal cortices that show a gradual increase in architectonic differentiation in a direction from the least differentiated orbital and medial limbic cortices toward the most differentiated cortices in the arcuate concavity. The results showed that the visual input to basoventral and mediodorsal prefrontal cortices originated largely in topographically distinct visual areas. Thus, basoventral sites received most of their visual cortical projections from the inferior temporal cortex. The rostral inferior temporal region was the predominant source of visual projections to orbital prefrontal sites, whereas lateral area 12 and ventral area 46 also received projections which were found more caudally. In contrast, mediodorsal prefrontal sites received most of their visual projections from dorsolateral and dorsomedial visual areas. The cells of origin were located in rostromedial visual cortices after injection of retrograde tracers in area 32 and in more caudal medial and dorsolateral visual areas after injection in caudal area 8. The latter also received substantial projections from visuomotor regions in the caudal portion of the lateral bank of the intraparietal sulcus. These results suggest that the basoventral prefrontal cortices are connected with ventral visual areas implicated in pattern recognition and discrimination, whereas the mediodorsal cortices are connected with medial and dorsolateral occipital and parietal areas associated with visuospatial functions. In addition, the prefrontal areas studied received projections from auditory and/or somatosensory cortices, from areas associated with more than one modality, and from limbic regions. Orbital area 12 seemed to be a major target of projections from somatosensory cortices and the rostral portion of medial area 32 received substantial projections from auditory cortices. The least architectonically differentiated areas (orbital area 11 and medial area 32) had more widespread corticocortical connections, including strong links with limbic cortices.(ABSTRACT TRUNCATED AT 400 WORDS)

Organization of subcortical pathways for sensory projections to the limbic cortex. I. Subcortical projections to the medial limbic cortex in the rat.

Subcortical afferent projections to the medial limbic cortex were examined in the rat by the use of retrograde axonal transport of horseradish peroxidase. Small iontophoretic injections of horseradish peroxidase were placed at various locations within the dorsal and ventral cingulate areas, the dorsal agranular and ventral granular divisions of the retrosplenial cortex and the presubiculum. Somata of afferent neurons in the thalamus and basal forebrain were identified by retrograde labeling. Each of the anterior thalamic nuclei was found to project to several limbic cortical areas, although not with equal density. The anterior dorsal nucleus projects primarily to the presubiculum and ventral retrosplenial cortex; the anterior ventral nucleus projects to the retrosplenial cortex and the presubiculum with apparently similar densities; and the anterior medial nucleus projects primarily to the cingulate areas. The projections from the lateral dorsal nucleus to these limbic cortical areas are organized in a loose topographic fashion. The projection to the presubiculum originates in the most dorsal portion of the lateral dorsal nucleus. The projection to the ventral retrosplenial cortex originates in rostral and medial portions of the nucleus, whereas afferents to the dorsal retrosplenial cortex originate in caudal portions of the lateral dorsal nucleus. The projection to the cingulate originates in the ventral portion of the lateral dorsal nucleus. Other projections from the thalamus originate in the intralaminar and midline nuclei, including the central lateral, central dorsal, central medial, paracentral, reuniens, and paraventricular nuclei, and the ventral medial and ventral anterior nuclei. In addition, projections to the medial limbic cortex from the basal forebrain originate in cells of the nucleus of the diagonal band. Projections to the presubiculum also originate in the medial septum. These results are discussed in regard to convergence of sensory and nonsensory information projecting to the limbic cortex and the types of visual and other sensory information that may be relayed to the limbic cortex by these projections.

Organization of subcortical pathways for sensory projections to the limbic cortex. II. Afferent projections to the thalamic lateral dorsal nucleus in the rat.

Afferent projections to the thalamic lateral dorsal nucleus were examined in the rat by the use of retrograde axonal transport techniques. Small iontophoretic injections of horseradish peroxidase were placed at various locations within the lateral dorsal nucleus, and the location and morphology of cells of origin of afferent projections were identified by retrograde labeling. For all cases examined, subcortical retrogradely labeled neurons were most prominent in the pretectal complex, the intermediate layers of the superior colliculus, and the ventral lateral geniculate nucleus. Labeled cells were also seen in the thalamic reticular nucleus and the zona incerta. Within the cerebral cortex, labeled cells were prominent in the retrosplenial areas (areas 29b, 29c, and 29d) and the presubiculum. Labeled cells were also seen in areas 17 and 18 of occipital cortex. Peroxidase injections in the dorsal lateral part of the lateral dorsal nucleus result in labeled neurons in all of the ipsilateral pretectal nuclei, but especially those that receive direct retinal afferents. Labeled cells were also seen in the ventral lateral geniculate nucleus and the rostral tip of laminae IV-VI of the superior colliculus. In contrast, peroxidase injections in ventral medial portions of the lateral dorsal nucleus result in fewer labeled pretectal cells, and these labeled cells are found exclusively in the pretectal nuclei that do not receive retinal afferents. Other labeled cells following injections in the rostral and medial portions of the lateral dorsal nucleus are seen contralaterally in the medial pretectal region and nucleus of the posterior commissure, and bilaterally in the rostral tips of laminae IV and V of the superior colliculus. Camera lucida drawings of HRP labeled cells reveal that projecting cells in each pretectal nucleus have a characteristic soma size and dendritic branching pattern. These results are discussed with regard to the type of sensory information that may reach the lateral dorsal nucleus and then be relayed on to the medial limbic cortex.

‘Non-specific’ cholinesterase-containing neurons of the dorsal thalamus project to medial limbic cortex

Thalamocortical neurons that contain ‘non-specific’ cholinesterase (ChE) were studied with cholinesterase histochemistry and experimental axonal tracing techniques in adult rats. In addition to the presence of ChEthat is ubiquitous in capillary endothelium, neurons that contain ChE are found in 3 distinct regions of the dorsal thalamus, the thalamic reuniens nucleus (Re), the anterior dorsal nucleus (AD) and a region that includes the lateral part of the central lateral nucleus (CL) and the ventral portion of the lateral dorsal nucleus (LD). ChE activity appears light in cerebral cortex in general but histochemical staining is slightly greater in neuropil of the cingulate gyrus. Anterograde transport techniques with autoradiology demonstrated that neurons in the LD-CL region project to anterior cingulate cortex and the dorsal retrosplenial area. anterograde degeneration techniques demonstrated that AD projects primarily to ventral retrosplenial cortex. Injections of horseradish peroxidase (HRP) in the anterior cingulate cortex resulted in double labeled cells (cells containing both ChE and HRP reaction products) primaruly in LD and CL. HRP injections into ventral retrosplenial cortex resulted in double labeled cells in AD and RE. HRP injections in the subiculum resulted in double labeled cells in Re. Lesions placed in the region of thalamocortical projections resulted in a loss of ChE in the ipsilateral cingulate gyrus, as measured both histochemically and enzymatically. The finding that neurons containing ChE project to medial limbic cortex suggests that the ChE may be involved in the function of the thalamocortical component of the limbic system.

Electrophysiological evidence for a projection from medial prefrontal and anterior limbic cortex toward the medial preoptic area in the cat.

Neurons in cat medial prefrontal cortex, anterior limbic cortex and possibly the indusium griseum were identified by antidromic invasion as having axonal projections towards the medial preoptic region, using both macro- and microstimulation techniques. These projecting axons were found to be of slow conduction velocity (0.2-4.8 m/s) and to in some cases also send branches towards the anteromedial thalamus, mediodorsal thalamus, ventromedial tegmentum, basolateral amygdala or medial forebrain bundle. Threshold-depth curves for axons excited by microstimulation in the medial preoptic region were very steep, with proportionality constants of 0.3-7.1 micron/microA. Calculations based on the threshold-depth curves confirmed that microstimulation was most probably only activating axons within the MPO, and current spread to lateral fibers of passage following macrostimulation in the MPO was not detected in the branching studies.

Prenatal development of nucleus basalis complex and related fiber systems in man: A histochemical study

To provide parameters for study of the “cholinergic” innervation of a human fetal cerebrum, we have analyzed the prenatal development of histochemical reactivity in the nucleus basalis complex (a magnocellular complex known to contain a high concentration of cholinergic perikarya). Brains from fetuses and premature infants ranging between 8 and 35 weeks of gestation were frozen cut and processed by the thiocholine method for the demonstration of acetylcholinesterase activity. Since no consistent results were obtained with inhibitors on the material younger than 15 weeks, the histochemical reactivity for early stages was expressed as the total cholinesterase reactivity. The first sign of histochemical differentiation of the basal telencephalon is the appearance of a dark cholinesterase reactive “spot” situated between the developing lenticular nucleus and basal telencephalon surface as early as 9 weeks of gestation. The first cholinesterase reactive bundle connects this reactive area (nucleus basalis complex anlage) with the strongly reactive fiber system situated along the dorsal side of the optic tract. During the next “stage” (10.5 weeks), there is a significant increase in the size of the nucleus basalis complex and strongly cholinesterase reactive neuropil occupies the sublenticular, diagonal and septal areas. At this stage we have seen two new cholinesterase-reactive bundles: one well developed cholinesterase reactive fiber stratum approaching (but not penetrating) the neocortical anlage through the external capsule and another minute bundle running towards the medial limbic cortex through the precommissural septum. The supraoptic fiber system can be traced now to the pregeniculate area and the tegmentum. At 15 weeks, the first acetylcholinesterase reactive perikarya appear and the nucleus basalis complex anlage becomes segregated into several strongly reactive territories, corresponding in position to the medial septal, diagonal and basal nuclei as defined on adjacent Nissl stained sections. At this stage, fibers from the nucleus basalis complex enter the “white” matter of frontal, temporal, parietal and occipital parts of the cerebral hemisphere via the external capsule. Between 15 and 18 weeks, acetylcholinesterase fibers spread throughout the “white” matter of the cerebral hemisphere. In the next “stage” (18–22 weeks), strongly reactive fibers can be followed from the nucleus basalis below the putamen and through the external capsule to the transient, synapse-rich subplate zone of frontal, temporal, parietal and occipital cortices. Fibers from rostromedial divisions of the nucleus basalis complex extend above the developing corpus callosum and form “limbic” bundles—longitudinal striae and the ventral cingulum or run below the corpus callosum as a part of the ventral fornix. These supracallosal fibers penetrate the dorsal archicortex and reach the subplate zone of the parahippocampal gyrus. In addition, strongly reactive fibers can be traced from the nucleus basalis complex to subcortical structures: the amygdaloid, putamen, caudate and the mediodorsal thalamic nuclei. Between 22 and 30 weeks (preterm infants age) there is a significant increase in the number of large, strongly reactive neuronal perikarya in all divisions of the nucleus basalis complex: rostromedial, intermediate and caudolateral. The most prominent part of the nucleus basalis complex is the nucleus basalis which contains the largest and the most numerous neurons. It can be divided into the small rostromedial part (pars diffusa), the main intermediate part (pars compacta) and the posterior lateral division which consists of numerous (7–10) cell aggregations (pars aggregata), the most rostral corresponding to the nucleus subputaminalis and the most caudal intermingling with the amygdala. Concomitantly, the strong acetylcholinesterase reactivity was observed in the deepest layers and in the marginal zone of the neocortex, parahippocampal gyrus and hippocampal formation. In conclusion, the nucleus basalis complex develops the earliest acetylcholinesterase activity in the telencephalon and sends widely distributed fibers to the anlage of neocortex and limbic cortex by the end of the second trimester of gestation. The development of cortical layer innervation coincides with the appearance of the “adult” pattern of topographical relationships. These results provide new data on the development of the nucleus basalis complex and on the early, prenatal “cholinergic” innervation of cerebral cortex. These findings also suggest developmental interaction of basal forebrain fibers with other cortical afferents and offer a new explanation for the anatomical substrate of regulation of behavioural states in the human preterm infant.

Distribution of ‘Non-specific’ cholinesterase-containing neurons in the dorsal thalamus of the rat

This report describes the distribution of histochemically identified 'non-specific' cholinesterase (ChE)-containing neurons in the dorsal thalamus of the rat. Juvenile or young adult Long-Evans or Sprague-Dawley rats were sacrificed by formalin perfusion. Some animals received systemic injections of 1.5-2.0 mg/kg DFP 4-24 h prior to sacrifice. Separate series of 50 micron frozen sections were processed for cholinesterase histochemistry using acetylthiocholine, butyrylthiocholine, or propionylthiocholine as substrates. Adjacent sections processed with each of the 3 substrates allowed comparison of the distributions of neurons containing the histochemical reaction products. Neurons containing moderate to high concentrations of ChE reaction product were found in 3 distinct regions of the dorsal thalamus. First, neurons staining intensely for ChE were found in a cluster that corresponds to the thalamic reuniens nucleus. Second, a cluster of neurons staining intensely for ChE was found in a region that included the lateral part of the central lateral nucleus and extended laterally into the ventral-lateral part of the lateral dorsal nucleus. Third, moderate ChE staining was observed in the neurons of the anterior dorsal nucleus. Of these regions, only the anterior dorsal nucleus shows moderate to high levels of acetylcholinesterase. The function of ChE in normal brain function is unknown. It is particularly interesting, however, that the thalamic nuclei containing ChE-positive neurons send thalamocortical projections to the medial limbic cortex, including cingulate, retrosplenial and subicular cortices.

Supplementary motor area structure and function: Review and hypotheses

AbstractThough its existence has been known for well over 30 years, only recently has the supplementary motor area (SMA) and its role in the cortical organization of movement come to be examined in detail by neuroscientists. Evidence from a wide variety of investigational perspectives is reviewed in an attempt to synthesize a conceptual framework for understanding SMA function. It is suggested that the SMA has an important role to play in the intentional process whereby internal context influences the elaboration of action. It may be viewed as phylogenetically older motor cortex, derived from anterior cingulate periarchicortical limbic cortex, which, as a key part of a medial premotor system, is crucial in the “programming” and fluent execution of extended action sequences which are “projectional” in that they rely on model-based prediction. This medial system can be distinguished from a lateral premotor system postulated to have evolved over phylogeny from a different neural source. An anatomico-physiologic model of the medial premotor system is proposed which embodies the principles of cyclicity and reentrance in the process of selecting those neural components to become active in conjunction with the performance of a particular action. The postulated dynamic action of this model in the microgenesis of a discrete action is outlined. It is concluded that although there is a great deal to be learned about the SMA, a convergence of current evidence can be identified. Such evidence suggests that the SMA plays an important role in the development of the intention-to-act and the specification and elaboration of action through its mediation between medial limbic cortex and primary motor cortex.