Increased intrinsic and synaptic excitability of hypothalamic POMC neurons underlies chronic stress-induced behavioral deficits.

Chronic stress exposure induces maladaptive behavioral responses and increases susceptibility to neuropsychiatric conditions. However, specific neuronal populations and circuits that are highly sensitive to stress and trigger maladaptive behavioral responses remain to be identified. Here we investigate the patterns of spontaneous activity of proopiomelanocortin (POMC) neurons in the arcuate nucleus (ARC) of the hypothalamus following exposure to chronic unpredictable stress (CUS) for 10 days, a stress paradigm used to induce behavioral deficits such as anhedonia and behavioral despair [1, 2]. CUS exposure increased spontaneous firing of POMC neurons in both male and female mice, attributable to reduced GABA-mediated synaptic inhibition and increased intrinsic neuronal excitability. While acute activation of POMC neurons failed to induce behavioral changes in non-stressed mice of both sexes, subacute (3 days) and chronic (10 days) repeated activation of POMC neurons was sufficient to induce anhedonia and behavioral despair in males but not females under non-stress conditions. Acute activation of POMC neurons promoted susceptibility to subthreshold unpredictable stress in both male and female mice. Conversely, acute inhibition of POMC neurons was sufficient to reverse CUS-induced anhedonia and behavioral despair in both sexes. Collectively, these results indicate that chronic stress induces both synaptic and intrinsic plasticity of POMC neurons, leading to neuronal hyperactivity. Our findings suggest that POMC neuron dysfunction drives chronic stress-related behavioral deficits.

Hypothalamic tanycytes generate acute hyperphagia through activation of the arcuate neuronal network.

Hypothalamic tanycytes are chemosensitive glial cells that contact the cerebrospinal fluid in the third ventricle and send processes into the hypothalamic parenchyma. To test whether they can activate neurons of the arcuate nucleus, we targeted expression of a Ca2+-permeable channelrhodopsin (CatCh) specifically to tanycytes. Activation of tanycytes ex vivo depolarized orexigenic (neuropeptide Y/agouti-related protein; NPY/AgRP) and anorexigenic (proopiomelanocortin; POMC) neurons via an ATP-dependent mechanism. In vivo, activation of tanycytes triggered acute hyperphagia only in the fed state during the inactive phase of the light-dark cycle.

Hypothalamic Structural and Functional Imbalances in Anorexia Nervosa.

The hypothalamus contains integrative systems that support life, including physiological processes such as food intake, energy expenditure, and reproduction. Here, we show that anorexia nervosa (AN) patients, contrary to normal weight and constitutionally lean individuals, respond with a paradoxical reduction in hypothalamic levels of glutamate/glutamine (Glx) upon feeding. This reversal of the Glx response is associated with decreased wiring in the arcuate nucleus and increased connectivity in the lateral hypothalamic area, which are involved in the regulation on a variety of physiological and behavioral functions including the control of food intake and energy balance. The identification of distinct hypothalamic neurochemical dysfunctions and associated structural variations in AN paves the way for the development of new diagnostic and treatment strategies in conditions associated with abnormal body mass index and a maladaptive response to negative energy balance.

Prenatal Testosterone Exposure Alters GABAergic Synaptic Inputs to GnRH and KNDy Neurons in a Sheep Model of Polycystic Ovarian Syndrome.

Prenatal testosterone (T)-treated female sheep display reproductive deficits similar to women with polycystic ovarian syndrome (PCOS), including an increase in LH pulse frequency due to actions of the central GnRH pulse generator. In this study, we used multiple-label immunocytochemistry to investigate the possibility of changes in the γ-aminobutyric acid (GABA) neurotransmitter system at two key components of the GnRH pulse generator in prenatal T-treated sheep: kisspeptin/neurokinin B/dynorphin (KNDy) neurons of the arcuate nucleus, and GnRH neurons in the preoptic area (POA) and mediobasal hypothalamus (MBH). We observed a significant decrease and increase, respectively, in the number of GABAergic synapses onto POA and MBH GnRH neurons in prenatal T-treated ewes; additionally, there was a significant increase in the number of GABAergic inputs onto KNDy neurons. To determine the actions of GABA on GnRH and KNDy neurons, we examined colocalization with the chloride transporters NKCC1 and KCC2, which indicate stimulatory or inhibitory activation of neurons by GABA, respectively. Most GnRH neurons in both POA and MBH colocalized NKCC1 cotransporter whereas none contained the KCC2 cotransporter. Most KNDy neurons colocalized either NKCC1 or KCC2, and 28% of the KNDy population contained NKCC1 alone. Therefore, we suggest that, as in the mouse, GABA in the sheep is stimulatory to GnRH neurons, as well as to a subset of KNDy neurons. Increased numbers of stimulatory GABAergic inputs to both MBH GnRH and KNDy neurons in prenatal T-treated animals may contribute to alterations in steroid feedback control and increased GnRH/LH pulse frequency seen in this animal model of PCOS.

Activation of arcuate nucleus GABA neurons promotes luteinizing hormone secretion and reproductive dysfunction: Implications for polycystic ovary syndrome.

BACKGROUND: Enhanced GABA activity in the brain and a hyperactive hypothalamic-pituitary-gonadal axis are associated with polycystic ovary syndrome (PCOS), the most common form of anovulatory infertility. Women with PCOS exhibit elevated cerebrospinal fluid GABA levels and preclinical models of PCOS exhibit increased GABAergic input to GnRH neurons, the central regulators of reproduction. The arcuate nucleus (ARN) is postulated as the anatomical origin of elevated GABAergic innervation; however, the functional role of this circuit is undefined. METHODS: We employed a combination of targeted optogenetic and chemogenetic approaches to assess the impact of acute and chronic ARN GABA neuron activation. Selective acute activation of ARN GABA neurons and their fiber projections was coupled with serial blood sampling for luteinizing hormone secretion in anesthetized male, female and prenatally androgenised (PNA) mice modelling PCOS. In addition, GnRH neuron responses to ARN GABA fiber stimulation were recorded in ex vivo brain slices. Chronic activation of ARN GABA neurons in healthy female mice was coupled with reproductive phenotyping for PCOS-like features. FINDINGS: Acute stimulation of ARN GABA fibers adjacent to GnRH neurons resulted in a significant and long-lasting increase in LH secretion in male and female mice. The amplitude of this response was blunted in PNA mice, which also exhibited a blunted LH response to GnRH administration. Infrequent and variable GABAA-dependent changes in GnRH neuron firing were observed in brain slices. Chronic activation of ARN GABA neurons in healthy females impaired estrous cyclicity, decreased corpora lutea number and increased circulating testosterone levels. INTERPRETATION: ARN GABA neurons can stimulate the hypothalamic-pituitary axis and chronic activation of ARN GABA neurons can mimic the reproductive deficits of PCOS in healthy females. Unexpectedly blunted HPG axis responses in PNA mice may reflect a history of high frequency GnRH/LH secretion and reduced LH stores, but also raise questions about impaired function within the ARN GABA population and the involvement of other circuits.

Persistent Leptin Signaling in the Arcuate Nucleus Impairs Hypothalamic Insulin Signaling and Glucose Homeostasis in Obese Mice.

BACKGROUND: Obesity is associated with reduced physiological responses to leptin and insulin, leading to the concept of obesity-associated hormonal resistance. OBJECTIVES: Here, we demonstrate that contrary to expectations, leptin signaling not only remains functional but also is constantly activated in the arcuate nucleus of the hypothalamus (ARH) neurons of obese mice. This state of persistent response to endogenous leptin underpins the lack of response to exogenous leptin. METHODS AND RESULTS: The study of combined leptin and insulin signaling demonstrates that there is a common pool of ARH neurons responding to both hormones. More importantly, we show that the constant activation of leptin receptor neurons in the ARH prevents insulin signaling in these neurons, leading to impaired glucose tolerance. Accordingly, antagonising leptin signaling in diet-induced obese (DIO) mice restores insulin signaling in the ARH and improves glucose homeostasis. Direct inhibition of PTP1B in the CNS restores arcuate insulin signaling similarly to leptin inhibition; this effect is likely to be mediated by AgRP neurons since PTP1B deletion specifically in AgRP neurons restores glucose and insulin tolerance in DIO mice. CONCLUSIONS: Finally, our results suggest that the constant activation of arcuate leptin signaling in DIO mice increases PTP1B expression, which exerts an inhibitory effect on insulin signaling leading to impaired glucose homeostasis.

Hypothalamic Obesity: Prologue and Promise.

Hypothalamic obesity (HO) frequently occurs following damage to the medial hypothalamic region, encompassing the arcuate nucleus, the paraventricular nucleus, the ventromedial nucleus, the dorsomedial nucleus, and the dorsal hypothalamic area, which are critically involved in the regulation of satiety and energy balance through neural and humoral connections. HO is most commonly described in the context of craniopharyngioma and its treatment, but it can also occur following other suprasellar tumors, radiation, trauma, or a surgical insult to the hypothalamus. A constellation of loss of satiety and a reduction of the metabolic rate, thermogenesis, and physical activity as well as increased vagal tone and hyperinsulinism with insulin and leptin resistance results in rapid weight gain due to a decreased energy expenditure and increased energy storage in adipose cells. To date, no viable long-term solution for HO has been found, due either to the requirement of intact hypothalamic pathways or to significant side effects. Newer therapeutic modalities focused on the unique pathophysiology of this condition offer potential for successful treatment. In this review, we describe the etiology of HO as well as past/current treatment approaches in the categories of hyperinsulinism, surgical approaches, and targeting energy expenditure/anorectic drugs. We conclude by providing an overview of the clinical trials currently underway.

Protective role of AgRP neuron's PDK1 against salt-induced hypertension.

In the hypothalamic arcuate nucleus (ARC), orexigenic agouti-related peptide (AgRP) neurons regulate feeding behavior and energy homeostasis. The 3-phosphoinositide-dependent protein kinase-1 (PDK1) in AgRP neurons serves as a major signaling molecule for leptin and insulin, the hormones regulating feeding behavior, energy homeostasis and circulation. However, it is unclear whether PDK1 in AGRP neurons is also involved in regulation of blood pressure. This study explored it by generating and analyzing AgRP neuron-specific PDK1 knockout (Agrp-Pdk1flox/flox) mice and effect of high salt diet on blood pressure in KO and WT mice was analyzed. Under high salt diet feeding, systolic blood pressure (SBP) of Agrp-Pdk1flox/flox mice was significantly elevated compared to Agrp-Cre mice. When the high salt diet was switched to control low salt diet, SBP of Agrp-Pdk1flox/flox mice returned to the basal level observed in Agrp-Cre mice within 1 week. In Agrp-Pdk1flox/flox mice, urinary noradrenalin excretion and NUCB2 mRNA expression in hypothalamic paraventricular nucleus (PVN) were markedly upregulated. Moreover, silencing of NUCB2 in the PVN counteracted the rises in urinary noradrenalin excretions and SBP. These results demonstrate a novel role of PDK1 in AgRP neurons to counteract the high salt diet-induced hypertension by preventing hyperactivation of PVN nesfatin-1 neurons.

Role of PTP1B in POMC neurons during chronic high-fat diet: sex differences in regulation of liver lipids and glucose tolerance.

Protein tyrosine phosphatase 1B (PTP1B) is a negative regulator of leptin receptor signaling and may contribute to leptin resistance in diet-induced obesity. Although PTP1B inhibition has been suggested as a potential weight loss therapy, the role of specific neuronal PTP1B signaling in cardiovascular and metabolic regulation and the importance of sex differences in this regulation are still unclear. In this study, we investigated the impact of proopiomelanocortin (POMC) neuronal PTP1B deficiency in cardiometabolic regulation in male and female mice fed a high-fat diet (HFD). When compared with control mice (PTP1B flox/flox), male and female mice deficient in POMC neuronal PTP1B (PTP1B flox/flox/POMC-Cre) had attenuated body weight gain (males: -18%; females: -16%) and fat mass (males: -33%; female: -29%) in response to HFD. Glucose tolerance was improved by 40%, and liver lipid accumulation was reduced by 40% in PTP1B/POMC-Cre males but not in females. When compared with control mice, deficiency of POMC neuronal PTP1B did not alter mean arterial pressure (MAP) in male or female mice (males: 112 ± 1 vs. 112 ± 1 mmHg in controls; females: 106 ± 3 vs. 109 ± 3 mmHg in controls). Deficiency of POMC neuronal PTP1B also did not alter MAP response to acute stress in males or females compared with control mice (males: Δ32 ± 0 vs. Δ29 ± 4 mmHg; females: Δ22 ± 2 vs. Δ27 ± 4 mmHg). These data demonstrate that POMC-specific PTP1B deficiency improved glucose tolerance and attenuated diet-induced fatty liver only in male mice and attenuated weight gain in males and females but did not enhance the MAP and HR responses to a HFD or to acute stress.

Long-term effects of sleep deprivation on neuronal activity in four hypothalamic areas.

Lack of adequate sleep has become increasingly common in our 24/7 society. Unfortunately diminished sleep has significant health consequences including metabolic and cardiovascular disease and mental disorders including depression. The pathways by which reduced sleep adversely affects physiology and behavior are unknown. We found that 6h of sleep deprivation in adult male rats induces changes in neuronal activity in the lateral hypothalamus, the paraventricular nucleus, the arcuate nucleus and the mammillary bodies. Surprisingly, these alterations last for up to 48h. The data show that sleep loss has prolonged effects on the activity of multiple hypothalamic areas. Our data indicate also that measuring electroencephalographic slow wave activity underestimates the amount of time that the hypothalamus requires to recover from episodes of sleep deprivation. We propose that these hypothalamic changes underlie the well-established relationship between sleep loss and several diseases such as metabolic disorders, stress and depression and that sufficient sleep is vital for autonomic functions controlled by the hypothalamus.

Impaired hypothalamic cocaine- and amphetamine-regulated transcript expression in lateral hypothalamic area and paraventricular nuclei of dehydration-induced anorexic rats.

Negative energy balance promotes physiological adaptations that ensure the survival of animals. The hypothalamic-pituitary-thyroid axis regulates basal energy expenditure and its down-regulating adaptation to negative energy balance is well described: in fasting, the serum content of thyrotrophin (TSH) and thyroid hormones (TH) decreases, enhancing the survival odds of individuals. By contrast, dehydration-induced anorexic (DIA) rats present an impaired hypothalamic-pituitary-thyroid (HPT) axis adaptation despite their negative energy balance: increased circulating TSH levels. The implication of cocaine- and amphetamine-regulated transcript (CART), an anorexic peptide, in HPT axis function impairment and food-avoidance behaviour displayed by DIA animals is unknown. Because CART is co-expressed with the peptide that regulates the HPT axis in hypophysiotrophic paraventricular nucleus (PVN) neurones (TSH-releasing hormone), we analysed CART expression and possible implications with respect to high TSH levels of DIA animals. We examined whether changes in CART expression from the lateral hypothalamic area (LHA) and arcuate nucleus (ARC) could participate in food-avoidance of DIA rats. DIA and forced-food restricted (FFR) animals reduced their body weight and food intake. FFR rats had a down-regulation of their HPT axis (reduced serum TH and TSH content), whereas DIA animals had reduced TH but increased TSH levels. CART mRNA expression in the ARC decreased similarly between experimental groups and diminished in anterior, medial PVN and in LHA of FFR animals, whereas DIA animals showed unchanged levels. This impaired CART mRNA expression in the anterior PVN and LHA could be related to the aberrant feeding behaviour of DIA rats but not to their deregulated HPT axis function.

Arcuate neuropeptide Y inhibits sympathetic nerve activity via multiple neuropathways.

Obesity increases sympathetic nerve activity (SNA) via activation of proopiomelanocortin neurons in the arcuate nucleus (ArcN), and this action requires simultaneous withdrawal of tonic neuropeptide Y (NPY) sympathoinhibition. However, the sites and neurocircuitry by which NPY decreases SNA are unclear. Here, using designer receptors exclusively activated by designer drugs (DREADDs) to selectively activate or inhibit ArcN NPY neurons expressing agouti-related peptide (AgRP) in mice, we have demonstrated that this neuronal population tonically suppresses splanchnic SNA (SSNA), arterial pressure, and heart rate via projections to the paraventricular nucleus (PVN) and dorsomedial hypothalamus (DMH). First, we found that ArcN NPY/AgRP fibers closely appose PVN and DMH presympathetic neurons. Second, nanoinjections of NPY or an NPY receptor Y1 (NPY1R) antagonist into PVN or DMH decreased or increased SSNA, respectively. Third, blockade of DMH NPY1R reversed the sympathoinhibition elicited by selective, DREADD-mediated activation of ArcN NPY/AgRP neurons. Finally, stimulation of ArcN NPY/AgRP terminal fields in the PVN and DMH decreased SSNA. Considering that chronic obesity decreases ArcN NPY content, we propose that the ArcN NPY neuropathway to the PVN and DMH is pivotal in obesity-induced elevations in SNA.

Role of Arcuate Nucleus in the Regulation of Feeding Behavior in the Process of Altitude Acclimatization in Rats.

Liu, Xiang-Wen, Jie Yin, Qi-Sheng Ma, Chu-Chu Qi, Ji-Ying Mu, Lang Zhang, Li-Ping Gao, and Yu-Hong Jing. Role of arcuate nucleus in the regulation of feeding behavior in the process of altitude acclimatization in rats. High Alt Med Biol. 18:234-241, 2017.-Highly efficient energy utilization and metabolic homeostasis maintenance rely on neuromodulation. Altitude exposure is known to stimulate neuroendocrine systems to respond to acute hypoxia and adaptive acclimatization. However, limited data on how the adaptive regulation of the arcuate nucleus performs in the process of altitude acclimatization are available. In the present study, male Sprague Dawley rats were transported to Huashixia, Qinghai (with an altitude of 4400 m) from Xian (with an altitude of 300 m) by air; rats were consistently raised in Xian as control. Food uptake and body weight were measured consecutively after being subjected to high-altitude condition. Contents of plasma leptin and ghrelin were analyzed by the Enzyme Linked Immunosorbent Assay (ELISA) Kits. Brain coronal sections were obtained, and neuropeptide Y (NPY), proopiomelanocotin (POMC), and c-fos immunoreactivity in arcuate nucleus were observed. Arcuate nucleus was isolated from the hypothalamus, and the mRNA of NPY and POMC were measured by quantitative real-time polymerase chain reaction. Our results showed both food consumption and body weight decreased in the high plateau compared with rats raised in the low-altitude condition. Plasma leptin increased at the early stage, and ghrelin decreased at a later stage after reaching the high plateau. The peak of c-fos immunoreactivity in the arcuate nucleus was at day 3 after reaching the high plateau. The expression level of NPY increased, and POMC decreased in the arcuate nucleus at day 7 after reaching the high plateau compared with the plain control group. These results indicate that the arcuate nucleus of hypothalamus performs an important function in regulating feeding behavior during altitude acclimatization. Our study suggested that altitude acclimation is regulated by the hypothalamus that received leptin and ghrelin signals to response by its microcircuit, including NPY- and POMC-neurons in the arcuate nucleus.

Suprachiasmatic Nucleus Interaction with the Arcuate Nucleus; Essential for Organizing Physiological Rhythms.

The suprachiasmatic nucleus (SCN) is generally considered the master clock, independently driving all circadian rhythms. We recently demonstrated the SCN receives metabolic and cardiovascular feedback adeptly altering its neuronal activity. In the present study, we show that microcuts effectively removing SCN-arcuate nucleus (ARC) interconnectivity in Wistar rats result in a loss of rhythmicity in locomotor activity, corticosterone levels, and body temperature in constant dark (DD) conditions. Elimination of these reciprocal connections did not affect SCN clock gene rhythmicity but did cause the ARC to desynchronize. Moreover, unilateral SCN lesions with contralateral retrochiasmatic microcuts resulted in identical arrhythmicity, proving that for the expression of physiological rhythms this reciprocal SCN-ARC interaction is essential. The unaltered SCN c-Fos expression following glucose administration in disconnected animals as compared to a significant decrease in controls demonstrates the importance of the ARC as metabolic modulator of SCN neuronal activity. Together, these results indicate that the SCN is more than an autonomous clock, and forms an essential component of a larger network controlling homeostasis. The present novel findings illustrate how an imbalance between SCN and ARC communication through circadian disruption could be involved in the etiology of metabolic disorders.

Prenatal Hyperhomocysteinemia Impairs Hypothalamic Regulation of Reproductive Cycles in Rat Progeny.

Effects of prenatal hyperhomocysteinemia on hypothalamic regulation of estrous cycles were studied in female rats. In mature rats exposed to prenatal hyperhomocysteinemia, changes in the catecholamine content in hypothalamic areas responsible for the formation of the preovulatory surge of gonadotropin-releasing hormone were revealed: the level of norepinephrine in the medial preoptic area decreased and concentration of dopamine in the median eminence with arcuate nuclei increased. Administration of melatonin attenuated the observed changes, which can be related to neuroprotective effects of this hormone determined by its antioxidant properties.

Nesfatin-1 regulates the lateral hypothalamic area melanin-concentrating hormone-responsive gastric distension-sensitive neurons and gastric function via arcuate nucleus innervation.

Nesfatin-1, a recently discovered neuropeptide involved in satiety. Recent studies have revealed that central nesfatin-1 inhibits gastric emptying and gastric acid secretion, though the mechanisms involved in these processes are not known. We aim to explore the effects of nesfatin-1 on a population of gastric distension (GD)-sensitive neurons in the lateral hypothalamus (LHA), gastric motility, and gastric secretion and the role for an arcuate nucleus (Arc)-LHA neural pathway in these processes. Single unit extracellular discharge recordings were made in of LHA. Further, gastric motility and gastric secretion in rats were monitored. Retrograde tracing and fluorescent immunohistochemical staining were used to explore nesfatin-1 neuron projection. The results revealed that administration of nesfatin-1 to the LHA or electric stimulation of the Arc could alter the neuronal activity of melanin-concentrating hormone (MCH)-responsive, GD-responsive neurons in LHA, which could be blocked by pretreatment with MCH receptor-1 antagonist PMC-3881-PI or weakened by pretreatment of a nesfatin-1 antibody in LHA. Administration of nesfatin-1 into LHA could inhibit gastric motility and gastric secretion, and these effects could be enhanced by administration of PMC-3881-PI. Electrical stimulation of Arc promoted the gastric motility and gastric secretion. Nesfatin-1 antibody or PMC-3881-PI pretreatment to LHA had no effect on Arc stimulation-induced gastric motility, but these pretreatments did alter Arc stimulation-induced effects on gastric secretion. Our findings suggest that nesfatin-1 signaling in LHA participates in the regulation of efferent information from the gastrointestinal tract and gastric secretion which also involve MCH signaling. Further, they show that a nesfatin-1-positive Arc to LHA pathway is critical for these effects.

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.

Recovery of injured Broca's portion of arcuate fasciculus in the dominant hemisphere in a patient with traumatic brain injury.

RATIONALE: Recovery of injured AF in patients with traumatic brain injury (TBI) has not been reported. In this study, we report on a patient with TBI who recovered from an injury to Broca's portion of AF in the dominant hemisphere, diagnosed by diffusion tensor tractography (DTT). PATIENT CONCERNS: A 28-year-old right-handed male patient suffered head trauma resulting from sliding while riding a motorcycle. DIAGNOSES: He was diagnosed with a traumatic contusional hemorrhage in the left frontal lobe, subarachnoid hemorrhage, and subdural hemorrhage in the left fronto-temporal lobe. INTERVENTIONS: He underwent craniectomy on the left fronto-temporal area, and hematoma removal for the subdural hemorrhage in the neurosurgery department of a university hospital. Two weeks after the injury, he was transferred to the rehabilitation department of another university hospital. He showed severe aphasia and brain MRI showed leukomalactic lesion in the left frontal lobe. OUTCOMES: The result WAB for the patient showed severe aphasia, with an aphasia quotient of 45.3 percentile. However, his aphasia improved rapidly by 9 months with an aphasia quotient at the 100.0 percentile. 2-week DTT detected discontinuity in the subcortical white matter at the branch to Broca's area of left AF. By contrast, on 9-month DTT, the discontinued portion of left AF was elongated to the left Broca's area. LESSONS: Recovery of injured Broca's portion of AF in the dominant hemisphere along with excellent improvement of aphasia was demonstrated in a patient with TBI. This study has important implications in brain rehabilitation because the mechanism of recovery from aphasia following TBI has not been elucidated.

QRFP-Deficient Mice Are Hypophagic, Lean, Hypoactive and Exhibit Increased Anxiety-Like Behavior.

How the hypothalamus transmits hunger information to other brain regions to govern whole brain function to orchestrate feeding behavior has remained largely unknown. Our present study suggests the importance of a recently found lateral hypothalamic neuropeptide, QRFP, in this signaling. Qrfp-/- mice were hypophagic and lean, and exhibited increased anxiety-like behavior, and were hypoactive in novel circumstances as compared with wild type littermates. They also showed decreased wakefulness time in the early hours of the dark period. Histological studies suggested that QRFP neurons receive rich innervations from neurons in the arcuate nucleus which is a primary region for sensing the body's metabolic state by detecting levels of leptin, ghrelin and glucose. These observations suggest that QRFP is an important mediator that acts as a downstream mediator of the arcuate nucleus and regulates feeding behavior, mood, wakefulness and activity.