Sexually dimorphic neuronal inputs to the neuroendocrine dopaminergic system governing prolactin release.

Prolactin (PRL) is a pleiotropic hormone that was identified in the context of maternal care and its release from the anterior pituitary is primarily controlled by neuroendocrine dopaminergic (NEDA) neurones of the arcuate nucleus of the hypothalamus. The sexually dimorphic nature of PRL physiology and associated behaviours is evident in mammals, even though the number and density of NEDA neurones is reported as not being sexually dimorphic in rats. However, the underlying circuits controlling NEDA neuronal activity and subsequent PRL release are largely uncharacterised. Thus, we mapped whole-brain monosynaptic NEDA inputs in male and female mice. Accordingly, we employed a rabies virus based monosynaptic tracing system capable of retrogradely mapping inputs into genetically defined neuronal populations. To gain genetic access to NEDA neurones, we used the dopamine transporter promoter. Here, we unravel 59 brain regions that synapse onto NEDA neurones and reveal that male and female mice, despite monomorphic distribution of NEDA neurones in the arcuate nucleus of the hypothalamus, receive sexually dimorphic amount of inputs from the anterior hypothalamic nucleus, anteroventral periventricular nucleus, medial preoptic nucleus, paraventricular hypothalamic nucleus, posterior periventricular nucleus, supraoptic nucleus, suprachiasmatic nucleus, lateral supramammillary nucleus, tuberal nucleus and periaqueductal grey. Beyond highlighting the importance of considering sex as a biological variable when evaluating connectivity in the brain, these results illustrate a case where a neuronal population with similar anatomical distribution has a subjacent sexually dimorphic connectivity pattern, potentially capable of contributing to the sexually dimorphic nature of PRL release and function.

Variability of the medullary arcuate nucleus in humans.

INTRODUCTION: The arcuate nucleus is a component of the ventral medullary surface involved in chemoreception and breathing control. The hypoplasia of this nucleus is a very frequent finding in victims of sudden unexplained fetal and infant death (from the last weeks of pregnancy to the first year of life). On the contrary, this developmental alteration is rarely present in age-matched controls who died of defined causes. These observations lead to hypothesize that a well-developed and functional arcuate nucleus is generally required to sustain life. The aim of this study was to investigate whether the arcuate nucleus maintains the same supposed function throughout life. METHODS: We carried out neuropathological examinations of brainstems obtained from 25 adult subjects, 18 males and 7 females, aged between 34 and 89 years, who died from various causes. RESULTS: For almost half of the cases (44%) microscopic examinations of serial histological sections of medulla oblongata showed a normal cytoarchitecture of the arcuate nucleus, extending along the pyramids. For the remaining 56% of cases, various degrees of hypodevelopment of this nucleus were observed, validated through the application of quantitative morphometric investigations, from decreased area, neuron number and volume, to full aplasia. CONCLUSIONS: These unexpected findings indicate that the involvement of the arcuate nucleus in chemoreception in adulthood is questionable, given the possibility of living until late age without this nucleus. This opens new perspectives for researchers on the role and function of the arcuate nucleus in humans from birth to old age.

Mapping the co-localization of the circadian proteins PER2 and BMAL1 with enkephalin and substance P throughout the rodent forebrain.

Despite rhythmic expression of clock genes being found throughout the central nervous system, very little is known about their function outside of the suprachiasmatic nucleus. Determining the pattern of clock gene expression across neuronal subpopulations is a key step in understanding their regulation and how they may influence the functions of various brain structures. Using immunofluorescence and confocal microscopy, we quantified the co-expression of the clock proteins BMAL1 and PER2 with two neuropeptides, Substance P (SubP) and Enkephalin (Enk), expressed in distinct neuronal populations throughout the forebrain. Regions examined included the limbic forebrain (dorsal striatum, nucleus accumbens, amygdala, stria terminalis), thalamus medial habenula of the thalamus, paraventricular nucleus and arcuate nucleus of the hypothalamus and the olfactory bulb. In most regions examined, BMAL1 was homogeneously expressed in nearly all neurons (~90%), and PER2 was expressed in a slightly lower proportion of cells. There was no specific correlation to SubP- or Enk- expressing subpopulations. The olfactory bulb was unique in that PER2 and BMAL1 were expressed in a much smaller percentage of cells, and Enk was rarely found in the same cells that expressed the clock proteins (SubP was undetectable). These results indicate that clock genes are not unique to specific cell types, and further studies will be required to determine the factors that contribute to the regulation of clock gene expression throughout the brain.

A molecular census of arcuate hypothalamus and median eminence cell types.

The hypothalamic arcuate-median eminence complex (Arc-ME) controls energy balance, fertility and growth through molecularly distinct cell types, many of which remain unknown. To catalog cell types in an unbiased way, we profiled gene expression in 20,921 individual cells in and around the adult mouse Arc-ME using Drop-seq. We identify 50 transcriptionally distinct Arc-ME cell populations, including a rare tanycyte population at the Arc-ME diffusion barrier, a new leptin-sensing neuron population, multiple agouti-related peptide (AgRP) and pro-opiomelanocortin (POMC) subtypes, and an orexigenic somatostatin neuron population. We extended Drop-seq to detect dynamic expression changes across relevant physiological perturbations, revealing cell type-specific responses to energy status, including distinct responses in AgRP and POMC neuron subtypes. Finally, integrating our data with human genome-wide association study data implicates two previously unknown neuron populations in the genetic control of obesity. This resource will accelerate biological discovery by providing insights into molecular and cell type diversity from which function can be inferred.

Sexual dimorphism of cardiopulmonary regulation in the arcuate nucleus of the hypothalamus.

The arcuate nucleus of the hypothalamus (ANH) interacts with other hypothalamic nuclei, forebrain regions, and downstream brain sites to affect autonomic nervous system outflow, energy balance, temperature regulation, sleep, arousal, neuroendocrine function, reproduction, and cardiopulmonary regulation. Compared to studies of other ANH functions, how the ANH regulates cardiopulmonary function is less understood. Importantly, the ANH exhibits structural and functional sexually dimorphic characteristics and contains numerous neuroactive substances and receptors including leptin, neuropeptide Y, glutamate, acetylcholine, endorphins, orexin, kisspeptin, insulin, Agouti-related protein, cocaine and amphetamine-regulated transcript, dopamine, somatostatin, components of renin-angiotensin system and gamma amino butyric acid that modulate physiological functions. Moreover, several clinically relevant disorders are associated with ANH ventilatory control dysfunction. This review highlights how ANH neurotransmitter systems and receptors modulate breathing differently in male and female rodents. Results highlight the significance of the ANH in cardiopulmonary regulation. The paucity of studies in this area that will hopefully spark investigations of sexually dimorphic ANH-modulation of breathing.

The Suprachiasmatic Nucleus Modulates the Sensitivity of Arcuate Nucleus to Hypoglycemia in the Male Rat.

The suprachiasmatic nucleus (SCN) and arcuate nucleus (ARC) have reciprocal connections; catabolic metabolic information activates the ARC and inhibits SCN neuronal activity. Little is known about the influence of the SCN on the ARC. Here, we investigated whether the SCN modulated the sensitivity of the ARC to catabolic metabolic conditions. ARC neuronal activity, as determined by c-Fos immunoreactivity, was increased after a hypoglycemic stimulus by 2-deoxyglucose (2DG). The highest ARC neuronal activity after 2DG was found at the end of the light period (zeitgeber 11, ZT11) with a lower activity in the beginning of the light period (zeitgeber 2, ZT2), suggesting the involvement of the SCN. The higher activation of ARC neurons after 2DG at ZT11 was associated with higher 2DG induced blood glucose levels as compared with ZT2. Unilateral SCN-lesioned animals, gave a mainly ipsilateral activation of ARC neurons at the lesioned side, suggesting an inhibitory role of the SCN on ARC neurons. The 2DG-induced counterregulatory glucose response correlated with increased ARC neuronal activity and was significantly higher in unilateral SCN-lesioned animals. Finally, the ARC as site where 2DG may, at least partly, induce a counterregulatory response was confirmed by local microdialysis of 2DG. 2DG administration in the ARC produced a higher increase in circulating glucose compared with 2DG administration in surrounding areas such as the ventromedial nucleus of the hypothalamus (VMH). We conclude that the SCN uses neuronal pathways to the ARC to gate sensory metabolic information to the brain, regulating ARC glucose sensitivity and counterregulatory responses to hypoglycemic conditions.

Arcuate fasciculus asymmetry has a hand in language function but not handedness.

The importance of relationships between handedness, language lateralization and localization, and white matter tracts for language performance is unclear. The goal of the study was to investigate these relationships by examining arcuate fasciculus (AF) structural asymmetry (DTI) and functional asymmetry (fMRI) in language circuits, handedness, and linguistic performance. A large sample of right-handed (n = 158) and atypical-handed (n = 82) healthy adults underwent DTI at 3 T to assess number of streamlines and fractional anisotropy (FA) of the AF, and language fMRI. Language functions were assessed using standard tests of vocabulary, naming, verbal fluency, and complex ideation. Laterality indices (LIs) illustrated degree of asymmetry and lateralization patterns for the AF (streamlines and FA) and verb generation fMRI. Both handedness groups showed leftward lateralization bias for streamline and fMRI LIs and symmetry for FA LI. The proportion of subjects with left, right, or symmetric lateralization were similar between groups if based on AF LIs, but differed if based on fMRI LIs (p = 0.0016). Degree of right-handedness was not associated with AF lateralization, but was associated with fMRI language lateralization (p = 0.0014). FA LI was not associated with performance on language assessments, but streamline LI was associated with better vocabulary and complex ideation performance in atypical-handed subjects (p = 0.022 and p = 0.0098, respectively), and better semantic fluency in right-handed subjects (p = 0.047); however, these did not survive multiple comparisons correction. We provide evidence that AF asymmetry is independent of hand preference, and while degree of right-handedness is associated with hemispheric language lateralization, the majority of atypical-handed individuals are left-lateralized for language. Hum Brain Mapp 37:3297-3309, 2016. © 2016 Wiley Periodicals, Inc.

Changes in the female arcuate nucleus morphology and neurochemistry after chronic ethanol consumption and long-term withdrawal.

Ethanol is a macronutrient whose intake is a form of ingestive behavior, sharing physiological mechanisms with food intake. Chronic ethanol consumption is detrimental to the brain, inducing gender-dependent neuronal damage. The hypothalamic arcuate nucleus (ARN) is a modulator of food intake that expresses feeding-regulatory neuropeptides, such as alpha melanocyte-stimulating hormone (α-MSH) and neuropeptide Y (NPY). Despite its involvement in pathways associated with eating disorders and ethanol abuse, the impact of ethanol consumption and withdrawal in the ARN structure and neurochemistry in females is unknown. We used female rat models of 20% ethanol consumption for six months and of subsequent ethanol withdrawal for two months. Food intake and body weights were measured. ARN morphology was stereologically analyzed to estimate its volume, total number of neurons and total number of neurons expressing NPY, α-MSH, tyrosine hydroxylase (TH) and estrogen receptor alpha (ERα). Ethanol decreased energy intake and body weights. However, it did not change the ARN morphology or the expression of NPY, α-MSH and TH, while increasing ERα expression. Withdrawal induced a significant volume and neuron loss that was accompanied by an increase in NPY expression without affecting α-MSH and TH expression. These findings indicate that the female ARN is more vulnerable to withdrawal than to excess alcohol. The data also support the hypothesis that the same pathways that regulate the expression of NPY and α-MSH in long-term ethanol intake may regulate food intake. The present model of long-term ethanol intake and withdrawal induces new physiological conditions with adaptive responses.

Fiber tracts of the dorsal language stream in the human brain.

OBJECT The aim of this study was to examine the arcuate (AF) and superior longitudinal fasciculi (SLF), which together form the dorsal language stream, using fiber dissection and diffusion imaging techniques in the human brain. METHODS Twenty-five formalin-fixed brains (50 hemispheres) and 3 adult cadaveric heads, prepared according to the Klingler method, were examined by the fiber dissection technique. The authors' findings were supported with MR tractography provided by the Human Connectome Project, WU-Minn Consortium. The frequencies of gyral distributions were calculated in segments of the AF and SLF in the cadaveric specimens. RESULTS The AF has ventral and dorsal segments, and the SLF has 3 segments: SLF I (dorsal pathway), II (middle pathway), and III (ventral pathway). The AF ventral segment connects the middle (88%; all percentages represent the area of the named structure that is connected to the tract) and posterior (100%) parts of the superior temporal gyri and the middle part (92%) of the middle temporal gyrus to the posterior part of the inferior frontal gyrus (96% in pars opercularis, 40% in pars triangularis) and the ventral premotor cortex (84%) by passing deep to the lower part of the supramarginal gyrus (100%). The AF dorsal segment connects the posterior part of the middle (100%) and inferior temporal gyri (76%) to the posterior part of the inferior frontal gyrus (96% in pars opercularis), ventral premotor cortex (72%), and posterior part of the middle frontal gyrus (56%) by passing deep to the lower part of the angular gyrus (100%). CONCLUSIONS This study depicts the distinct subdivision of the AF and SLF, based on cadaveric fiber dissection and diffusion imaging techniques, to clarify the complicated language processing pathways.

The direct segment of the arcuate fasciculus is predictive of longitudinal reading change.

Structural coherence across the arcuate fasciculus has previously been related to reading skill, but the arcuate may be divisible into distinct subtracts which support different functions. Here, we examine longitudinal data from 30 children between the ages of 8 and 14 to determine whether initial coherence in any of the arcuate's subsections is predictive of changes in reading across a longitudinal interval of approximately three years. The arcuate was divided using probabilistic tractography; mean fractional anisotropy across each subtract was extracted for each participant. Time 1 to Time 2 change in reading skill (identification, fluency score average) was significantly and uniquely predicted by only direct fronto-temporal arcuate segment coherence. Participants with lower direct segment FA demonstrated decreases in reading scores, potentially reflecting lessened improvements due to continued inefficient processing. These results were consistent in the older and younger halves of the sample. As such, we demonstrate that it is specifically the direct segment of the arcuate that may support and be predictive of reading skill both initially and longitudinally across development.

Neuropeptide Y activity in the nucleus accumbens modulates feeding behavior and neuronal activity.

BACKGROUND: Neuropeptide Y (NPY) is a hypothalamic neuropeptide that plays a prominent role in feeding and energy homeostasis. Expression of the NPY Y1 receptor (Y1R) is highly concentrated in the nucleus accumbens (Acb), a region important in the regulation of palatable feeding. In this study, we performed a number of experiments to investigate the actions of NPY in the Acb. METHODS: First, we determined caloric intake and food choice after bilateral administration of NPY in the Acb in rats on a free-choice diet of saturated fat, 30% sucrose solution, and standard chow and whether this was mediated by the Y1R. Second, we measured the effect of intra-Acb NPY on neuronal activity using in vivo electrophysiology. Third, we examined co-localization of Y1R with enkephalin and dynorphin neurons and the effect of NPY on preproenkephalin messenger RNA levels in the striatum using fluorescent and radioactive in situ hybridization. Finally, using retrograde tracing, we examined whether NPY neurons in the arcuate nucleus projected to the Acb. RESULTS: In rats on the free-choice, high-fat, high-sugar diet, intra-Acb NPY increased intake of fat, but not sugar or chow, and this was mediated by the Y1R. Intra-Acb NPY reduced neuronal firing, as well as preproenkephalin messenger RNA expression in the striatum. Moreover, Acb enkephalin neurons expressed Y1R and arcuate nucleus NPY neurons projected to the Acb. CONCLUSIONS: NPY reduces neuronal firing in the Acb resulting in increased palatable food intake. Together, our neuroanatomical, pharmacologic, and neuronal activity data support a role and mechanism for intra-Acb NPY-induced fat intake.

Influence of the hypothalamic arcuate nucleus on intraocular pressure and the role of opioid peptides.

BACKGROUND: An opioid peptide neuron/humoral feedback regulation might be involved in changes of intraocular pressure (IOP). The aims of this study are to investigate the effects of arcuate nucleus (ARC) and opioid peptides on intraocular pressure (IOP). METHODS: Fifty-four healthy purebred New Zealand white rabbits (108 eyes) were randomly divided into 4 groups, including control group, electrical stimulation group, [D-Ala2, N-Me-Phe4, Gly5-ol]-enkephalin (DAMGO) group, and [D-Pen 2, D-Pen5]- enkephalin (DPDPE) group. Bilateral IOP was measured after unilateral electrical stimulation of the ARC or unilateral microinjection into the ARC of the selective µ-opioid receptor agonist DAMGO or the selective δ opioid receptor agonist DPDPE, both alone and after pre-administration of either the non-selective opioid receptor antagonist naloxone or saline. RESULTS: Both electrical stimulation in ARC and micro-injection either or opioid receptor agonists, DAMGO or DPDPE, respectively, caused a significant bilateral reduction in IOP (P<0.05) which was more pronounced in the ipsilateral than in the contralateral eye. Pretreatment with naloxone prevented some, but not all IOP reductions. CONCLUSION: The ARC takes part in the negative regulation of IOP, an action that may involve opioid neurons.

Evaluating the arcuate fasciculus with combined diffusion-weighted MRI tractography and electrocorticography.

The conventional model of language-related brain structure describing the arcuate fasciculus as a key white matter tract providing a direct connection between Wernicke's region and Broca's area has been called into question. Specifically, the inferior precentral gyrus, possessing both primary motor (Brodmann Area [BA] 4) and premotor cortex (BA 6), has been identified as a potential alternative termination. The authors initially localized cortical sites involved in language using measurement of event-related gamma-activity on electrocorticography (ECoG). The authors then determined whether language-related sites of the temporal lobe were connected, via white matter structures, to the inferior frontal gyrus more tightly than to the precentral gyrus. The authors found that language-related sites of the temporal lobe were far more likely to be directly connected to the inferior precentral gyrus through the arcuate fasciculus. Furthermore, tractography was a significant predictor of frontal language-related ECoG findings. Analysis of an interaction between anatomy and tractography in this model revealed tractrography to have the highest predictive value for language-related ECoG findings of the precentral gyrus. This study failed to support the conventional model of language-related brain structure. More feasible models should include the inferior precentral gyrus as a termination of the arcuate fasciculus. The exact functional significance of direct connectivity between temporal language-related sites and the precentral gyrus requires further study.

Neuroanatomy of the kisspeptin signaling system in mammals: comparative and developmental aspects.

Our understanding of kisspeptin and its actions depends, in part, on a detailed knowledge of the neuroanatomy of the kisspeptin signaling system in the brain. In this chapter, we will review our current knowledge of the distribution of kisspeptin cells, fibers, and receptors in the mammalian brain, including the development, phenotype, and projections of different kisspeptin subpopulations. A fairly consistent picture emerges from this analysis. There are two major groups of kisspeptin cell bodies: a large number in the arcuate nucleus (ARC) and a smaller collection in the rostral periventricular area of the third ventricle (RP3V) of rodents and preoptic area (POA) of non-rodents. Both sets of neurons project to GnRH cell bodies, which contain Kiss1r, and the ARC kisspeptin population also projects to GnRH axons in the median eminence. ARC kisspeptin neurons contain neurokinin B and dynorphin, while a variable percentage of those cells in the RP3V of rodents contain galanin and/or dopamine. Neurokinin B and dynorphin have been postulated to contribute to the control of GnRH pulses and sex steroid negative feedback, while the role of galanin and dopamine in rostral kisspeptin neurons is not entirely clear. Kisspeptin neurons, fibers, and Kiss1r are found in other areas, including widespread areas outside the hypothalamus, but their physiological role(s) in these regions remains to be determined.

MC4R dimerization in the paraventricular nucleus and GHSR/MC3R heterodimerization in the arcuate nucleus: is there relevance for body weight regulation?

The worldwide obesity epidemic is increasing, yet at this time, no long-acting and specific pharmaceutical therapies are available. Peripheral hormonal signals communicate metabolic status to the hypothalamus by activating their corresponding receptors in the arcuate nucleus (ARC). In this brain region, a variety of G protein-coupled receptors (GPCRs) are expressed that are potentially involved in weight regulation, but so far, the detailed function of most hypothalamic GPCRs is only partially understood. An important and underappreciated feature of GPCRs is the capacity for regulation via di- and heterodimerization. Increasing evidence implicates that heterodimerization of GPCRs results in profound functional consequences. Recently, we could demonstrate that interaction of the melanocortin 3 receptor (MC3R) and the growth hormone secretagogue receptor (GHSR)-1a results in a modulation of function in both receptors. Although the physiological role of GPCR-GPCR interaction in the hypothalamus is yet to be elucidated, this concept promises new avenues for investigation and understanding of hypothalamic functions dependent on GPCR signaling. Since GPCRs are important targets for drugs to combat many diseases, identification of heterodimers may be a prerequisite for highly specific drugs. Therefore, a detailed understanding of the mechanisms and their involvement in weight regulation is necessary. Fundamental to this understanding is the interplay of GPCR-GPCR in the hypothalamic nuclei in energy metabolism. In this review, we summarize the current knowledge on melanocortin receptors and GHSR-1a in hypothalamic weight regulation, especially as they pertain to possible drug targets. Furthermore, we include available evidence for the participation and significance of GPCR dimerization.

The arcuate nucleus of the C57BL/6J mouse hindbrain is a displaced part of the inferior olive.

The arcuate nucleus is a prominent cell group in the human hindbrain, characterized by its position on the pial surface of the pyramid. It is considered to be a precerebellar nucleus and has been implicated in the pathology of several disorders of respiration. An arcuate nucleus has not been convincingly demonstrated in other mammals, but we have found a similarly positioned nucleus in the C57BL/6J mouse. The mouse arcuate nucleus consists of a variable group of neurons lying on the pial surface of the pyramid. The nucleus is continuous with the ventrolateral part of the principal nucleus of the inferior olive and both groups are calbindin positive. At first we thought that this mouse nucleus was homologous with the human arcuate nucleus, but we have discovered that the neurons of the human nucleus are calbindin negative, and are therefore not olivary in nature. We have compared the mouse arcuate neurons with those of the inferior olive in terms of molecular markers and cerebellar projection. The neurons of the arcuate nucleus and of the inferior olive share three major characteristics: they both contain neurons utilizing glutamate, serotonin or acetylcholine as neurotransmitters; they both project to the contralateral cerebellum, and they both express a number of genes not present in the major mossy fiber issuing precerebellar nuclei. Most importantly, both cell groups express calbindin in an area of the ventral hindbrain almost completely devoid of calbindin-positive cells. We conclude that the neurons of the hindbrain mouse arcuate nucleus are a displaced part of the inferior olive, possibly separated by the caudal growth of the pyramidal tract during development. The arcuate nucleus reported in the C57BL/6J mouse can therefore be regarded as a subgroup of the rostral inferior olive, closely allied with the ventral tier of the principal nucleus.

Arcuate fasciculus variability and repetition: the left sometimes can be right.

Repetition ability is a major criterion for classifying aphasic syndromes and its status is helpful in the determination of the involved neural structures. It is widely assumed that repetition deficits correlate with injury to the left perisylvian core including the arcuate fasciculus (AF). However, descriptions of normal repetition despite damage to the AF or impaired repetition without AF involvement cast doubts on its role in repetition. To explain these paradoxes, we analyse two different aphasic syndromes - in which repetition is selectively impaired (conduction aphasia) or spared (transcortical aphasias) - in light of recent neuroimaging findings. We suggest that the AF and other white matter bundles are the anatomical signatures of language repetition and that individual variability in their anatomy and lateralisation may explain negative cases.

The serotonergic anatomy of the developing human medulla oblongata: implications for pediatric disorders of homeostasis.

The caudal serotonergic (5-HT) system is a critical component of a medullary "homeostatic network" that regulates protective responses to metabolic stressors such as hypoxia, hypercapnia, and hyperthermia. We define anatomically the caudal 5-HT system in the human medulla as 5-HT neuronal cell bodies located in the raphé (raphé obscurus, raphé magnus, and raphé pallidus), extra-raphé (gigantocellularis, paragigantocellularis lateralis, intermediate reticular zone, lateral reticular nucleus, and nucleus subtrigeminalis), and ventral surface (arcuate nucleus). These 5-HT neurons are adjacent to all of the respiratory- and autonomic-related nuclei in the medulla where they are positioned to modulate directly the responses of these effector nuclei. In the following review, we highlight the topography and development of the caudal 5-HT system in the human fetus and infant, and its inter-relationships with nicotinic, GABAergic, and cytokine receptors. We also summarize pediatric disorders in early life which we term "developmental serotonopathies" of the caudal (as well as rostral) 5-HT domain and which are associated with homeostatic imbalances. The delineation of the development and organization of the human caudal 5-HT system provides the critical foundation for the neuropathologic elucidation of its disorders directly in the human brain.

Effects of chronic weight perturbation on energy homeostasis and brain structure in mice.

Maintenance of reduced body weight in lean and obese human subjects results in the persistent decrease in energy expenditure below what can be accounted for by changes in body mass and composition. Genetic and developmental factors may determine a central nervous system (CNS)-mediated minimum threshold of somatic energy stores below which behavioral and metabolic compensations for weight loss are invoked. A critical question is whether this threshold can be altered by environmental influences and by what mechanisms such alterations might be achieved. We examined the bioenergetic, behavioral, and CNS structural responses to weight reduction of diet-induced obese (DIO) and never-obese (CON) C57BL/6J male mice. We found that weight-reduced (WR) DIO-WR and CON-WR animals showed reductions in energy expenditure, adjusted for body mass and composition, comparable (-10-15%) to those seen in human subjects. The proportion of excitatory synapses on arcuate nucleus proopiomelanocortin neurons was decreased by ∼50% in both DIO-WR and CON-WR mice. These data suggest that prolonged maintenance of an elevated body weight (fat) alters energy homeostatic systems to defend a higher level of body fat. The synaptic changes could provide a neural substrate for the disproportionate decline in energy expenditure in weight-reduced individuals. This response to chronic weight elevation may also occur in humans. The mouse model described here could help to identify the molecular/cellular mechanisms underlying both the defense mechanisms against sustained weight loss and the upward resetting of those mechanisms following sustained weight gain.

Partition-based mass clustering of tractography streamlines.

We describe a novel scalable clustering framework for streamlines obtained from diffusion tractography. Clustering is an attractive means of segmenting a large set of streamlines into anatomically relevant bundles. For most existing methods, however, the large datasets produced in high resolution or multiple subject studies are problematical. To achieve good scalability, our method repeatedly divides the data into subsets, which are then partitioned using hierarchical clustering. A final partition is obtained by recombining the subsets. In addition, the recombination scheme provides a consistency measure for cluster assignment of individual streamlines, which is used to clean up the final result. The clusters have good anatomical plausibility and we show that three clusters corresponding to the three known segments of the arcuate fasciculus show excellent agreement with literature. A major advantage of the method is the fact that it can find clusters in datasets of essentially arbitrary size. This fact is exploited to find consistent clusters in concatenated tractography data from multiple subjects. We expect the identification of bundles across subjects to be an important application of the method.