Selective Rapid Eye Movement Sleep Deprivation Affects Cell Size and Number in Kitten Locus Coeruleus

Cells in the locus coeruleus (LC) constitute the sole source of norepinephrine (NE) in the brain and change their discharge rates according to vigilance state. In addition to its well established role in vigilance, NE affects synaptic plasticity in the postnatal critical period (CP) of development. One form of CP synaptic plasticity affected by NE results from monocular occlusion, which leads to physiological and cytoarchitectural alterations in central visual areas. Selective suppression of rapid eye movement sleep (REMS) in the CP kitten enhances the central effects of monocular occlusion. The mechanisms responsible for heightened cortical plasticity following REMS deprivation (REMSD) remain undetermined. One possible mediator of an increase in plasticity is continuous NE outflow, which presumably persists during extended periods of REMSD. Tyrosine hydroxylase (TH) is the rate-limiting enzyme in the synthesis of NE and serves as a marker for NE-producing cells. We selectively suppressed REMS in kittens for 1 week during the CP. The number and size of LC cells expressing immunoreactivity to tyrosine hydroxylase (TH-ir) was assessed in age-matched REMS-deprived (RD)-, treatment–control (TXC)-, and home cage-reared (HCC) animals. Sleep amounts and slow wave activity (SWA) were also examined relative to baseline. Time spent in REMS during the study was lower in RD compared to TXC animals, and RD kittens increased SWA delta power in the latter half of the REMSD period. The estimated total number of TH-ir cells in LC was significantly lower in the RD than in the TXC kittens and numerically lower than in the HCC animals. The size of LC cells expressing TH-ir was greatest in the HCC group. HCC cells were significantly larger than TH-ir cells in the RD kittens. These data are consistent with presumed reduction in NE in forebrain areas, including visual cortex, caused by 1 week of REMSD

The von Economo neurons in frontoinsular and anterior cingulate cortex in great apes and humans

The von Economo neurons (VENs) are large bipolar neurons located in frontoinsular (FI) and anterior cingulate cortex in great apes and humans, but not other primates. We performed stereological counts of the VENs in FI and LA (limbic anterior, a component of anterior cingulate cortex) in great apes and in humans. The VENs are more numerous in humans than in apes, although one gorilla approached the lower end of the human range. We also examined the ontological development of the VENs in FI and LA in humans. The VENs first appear in small numbers in the 36th week post-conception, are rare at birth, and increase in number during the first 8 months after birth. There are significantly more VENs in the right hemisphere than in the left in FI and LA in postnatal brains of apes and humans. This asymmetry in VEN numbers may be related to asymmetries in the autonomic nervous system. The activity of the inferior anterior insula, which contains FI, is related to physiological changes in the body, decision-making, error recognition, and awareness. The VENs appear to be projection neurons, although their targets are unknown. We made a preliminary study of the connections of FI cortex based on diffusion tensor imaging in the brain of a gorilla. The VEN-containing regions connect to the frontal pole as well as to other parts of frontal and insular cortex, the septum, and the amygdala. It is likely that the VENs in FI are projecting to some or all of these structures and relaying information related to autonomic control, decision-making, or awareness. The VENs selectively express the bombesin peptides neuromedin B (NMB) and gastrin releasing peptide (GRP) which are also expressed in another population of closely related neurons, the fork cells. NMB and GRP signal satiety. The genes for NMB and GRP are expressed selectively in small populations of neurons in the insular cortex in mice. These populations may be related to the VEN and fork cells and may be involved in the regulation of appetite. The loss of these cells may be related to the loss of satiety signaling in patients with frontotemporal dementia who have damage to FI. The VENs and fork cells may be morphological specializations of an ancient population of neurons involved in the control of appetite present in the insular cortex in all mammals. We found that the protein encoded by the gene DISC1 (disrupted in schizophrenia) is preferentially expressed by the VENs. DISC1 has undergone rapid evolutionary change in the line leading to humans, and since it suppresses dendritic branching it may be involved in the distinctive VEN morphology

Treatment with bexarotene, a compound that increases apolipoprotein-E, provides no cognitive benefit in mutant APP/PS1 mice

BACKGROUND: Though the precise cause(s) of Alzheimer’s disease (AD) remain unknown, there is strong evidence that decreased clearance of β-amyloid (Aβ) from the brain can contribute to the disease. Therapeutic strategies to promote natural Aβ clearance mechanisms, such as the protein apolipoprotein-E (APOE), hold promise for the treatment of AD. The amount of APOE in the brain is regulated by nuclear receptors including retinoid X receptors (RXRs). Drugs that activate RXRs, including bexarotene, can increase APOE and ABCA1 production, and have been shown to decrease the Aβ burden and improve cognition in mouse models of Aβ amyloidosis. Although recent bexarotene studies failed to replicate the rapid clearance of Aβ from brains, behavioral and cognitive effects of this compound remain controversial. FINDINGS: In efforts to clarify these behavioral findings, mutant APP/PS1 mice were acutely dosed with bexarotene. While ABCA1 was upregulated in mutant APP/PS1 mice treated with bexarotene, this drug failed to attenuate Aβ plaques or cognitive deficits in these mice. CONCLUSIONS: We recommend rigorous preclinical study to evaluate the mechanism and utility of such a compound for AD therapy

Comparative anatomy of the locus coeruleus in humans and nonhuman primates

The locus coeruleus (LC) is a dense cluster of neurons that projects axons throughout the neuroaxis and is located in the rostral pontine tegmentum extending from the level of the inferior colliculus to the motor nucleus of the trigeminal nerve. LC neurons are lost in the course of several neurodegenerative disorders, including Alzheimer's and Parkinson's diseases. In this study we used Nissl staining and tyrosine hydroxylase (TH) immunoreactivity to compare the human LC with that of closely related primate species, including great and lesser apes, and macaque monkeys. TH catalyzes the initial and rate-limiting step in catecholamine biosynthesis. The number of TH-immunoreactive (TH-ir) neurons was estimated in each species using stereologic methods. In the LC of humans the mean total number of TH-ir neurons was significantly higher compared to the other primates. Because the total number of TH-ir neurons in the LC was highly correlated with the species mean volume of the medulla oblongata, cerebellum, and neocortical gray matter, we conclude that much of the observed phylogenetic variation can be explained by anatomical scaling. Notably, the total number of LC neurons in humans was most closely predicted by the nonhuman allometric scaling relationship relative to medulla size, whereas the number of LC neurons in humans was considerably lower than predicted according to neocortex and cerebellum volume

The von Economo neurons in the frontoinsular and anterior cingulate cortex

The von Economo neurons (VENs) are large bipolar neurons located in the frontoinsular cortex (FI) and limbic anterior (LA) area in great apes and humans but not in other primates. Our stereological counts of VENs in FI and LA show them to be more numerous in humans than in apes. In humans, small numbers of VENs appear the 36th week postconception, with numbers increasing during the first 8 months after birth. There are significantly more VENs in the right hemisphere in postnatal brains; this may be related to asymmetries in the autonomic nervous system. VENs are also present in elephants and whales and may be a specialization related to very large brain size. The large size and simple dendritic structure of these projection neurons suggest that they rapidly send basic information from FI and LA to other parts of the brain, while slower neighboring pyramids send more detailed information. Selective destruction of VENs in early stages of frontotemporal dementia (FTD) implies that they are involved in empathy, social awareness, and self‐control, consistent with evidence from functional imaging

The von Economo neurons in the frontoinsular and anterior cingulate cortex

The von Economo neurons (VENs) are large bipolar neurons located in the frontoinsular cortex (FI) and limbic anterior (LA) area in great apes and humans but not in other primates. Our stereological counts of VENs in FI and LA show them to be more numerous in humans than in apes. In humans, small numbers of VENs appear the 36th week postconception, with numbers increasing during the first 8 months after birth. There are significantly more VENs in the right hemisphere in postnatal brains; this may be related to asymmetries in the autonomic nervous system. VENs are also present in elephants and whales and may be a specialization related to very large brain size. The large size and simple dendritic structure of these projection neurons suggest that they rapidly send basic information from FI and LA to other parts of the brain, while slower neighboring pyramids send more detailed information. Selective destruction of VENs in early stages of frontotemporal dementia (FTD) implies that they are involved in empathy, social awareness, and self‐control, consistent with evidence from functional imaging

Selective reduction of Von Economo neuron number in agenesis of the corpus callosum

Von Economo neurons (VENs) are large spindle-shaped neurons localized to anterior cingulate cortex (ACC) and fronto-insular cortex (FI). VENs appear late in development in humans, are a recent phylogenetic specialization, and are selectively destroyed in frontotemporal dementia, a disease which profoundly disrupts social functioning and self-awareness. Agenesis of the corpus callosum (AgCC) is a congenital disorder that can have significant effects on social and emotional behaviors, including alexithymia, difficulty intuiting the emotional states of others, and deficits in self- and social-awareness that can impair humor, comprehension of non-literal or affective language, and social judgment. To test the hypothesis that VEN number is selectively reduced in AgCC, we used stereology to obtain unbiased estimates of total neuron number and VEN number in postmortem brain specimens of four normal adult controls, two adults with isolated callosal dysgenesis, and one adult whose corpus callosum and ACC were severely atrophied due to a non-fatal cerebral arterial infarction. The partial agenesis case had approximately half as many VENs as did the four normal controls, both in ACC and FI. In the complete agenesis case the VENs were almost entirely absent. The percentage of neurons in FI that are VENs was reduced in callosal agenesis, but was actually slightly above normal in the stroke patient. These results indicate that the VEN population is selectively reduced in AgCC, but that the VENs do not depend on having an intact corpus callosum. We conclude that in agenesis of the corpus callosum the reduction in the number of VENs is not the direct result of the failure of this structure to develop, but may instead be another consequence of the genetic disruption that caused the agenesis. The reduction of the VEN population could help to explain some of the social and emotional deficits that are seen in this disorder