Circling Behavior Research Articles

Clozapine does not require 5-HT1A receptors to block the locomotor hyperactivity induced by MK-801

5-HT(1A) receptors mediate some effects of atypical antipsychotic drugs, such as the increase in cortical dopaminergic function, an effect likely related to the superior efficacy of these drugs on negative symptoms and cognitive deficits of schizophrenia. To examine whether 5-HT(1A) receptors are involved in the therapeutic action of clozapine (Clz) on positive symptoms, here we examined the ability of Clz to antagonize the behavioural syndrome induced by the non-competitive N-methyl-d-aspartate receptor antagonist, MK-801 in wild-type (WT) and 5-HT(1A)-receptor knockout (KO(1A)) mice. MK-801 administration induced hyperlocomotion, ataxia, stereotypies and an alteration of the locomotor pattern in both genotypes. However, some symptoms of the behavioural syndrome induced by MK-801 were less intense in KO(1A) mice compared with wild-type mice. Clz antagonized the majority of MK-801-induced effects in both strains of mice. No differences between genotypes were noted for the ability of Clz to antagonize the hyperlocomotion, yet Clz was more effective in preventing the increased activation time, short movements, circling behaviour and hind-limb abduction in KO(1A) mice. The present results indicate that 5-HT(1A) receptors do not play a critical role in Clz-induced antagonism of the main hyperactivity signs evoked by MK-801, suggesting that 5-HT(1A) receptors are not involved in the therapeutic action of Clz on positive symptoms of schizophrenia.

Genetic modification of the inner ear lateral semicircular canal phenotype of the Bmp4 haplo-insufficient mouse

In the mouse, development of the lateral semicircular canal of the inner ear is sensitive to Bmp4 heterozygosity. In the C57BL6 background 30% of the heterozygotes display circling behavior, 66% have a specific defect in the vestibular part of the inner ear, namely the constriction, interruption or absence of the lateral semicircular canal. Only mice having both ears affected display circling behavior. In the (C57BL6xCBA)N1 background, the penetrance of the canal phenotype is greatly reduced, and bilateral lateral canal defect is not sufficient to induce circling. We found association of the canal phenotype with the genotype of markers on chromosome 14 and 4, co-localizing with Ecs and Eclb identified in the Ecl mouse with similar lateral canal defects. Candidate genes to contain the causal mutation are Bmp4 on chromosome 14, and Rere on chromosome 4.

Nicardipine, a calcium antagonist, does not aggravate intracerebral haemorrhage in an intracerebral haemorrhage model in rats

Despite controversy over their safety in patients with intracerebral haemorrhage, calcium antagonists are widely used in the treatment of hypertensive emergencies. Here, we investigated the effects of nicardipine on haematoma size and neurological deficit in a rat model of collagenase-induced intracerebral haemorrhage. Injection of collagenase (0.014 U) into the striatum induced haematoma (19.9+/-3.4 mm(3)) in the striatum and brain oedema. Drugs were infused from 30 min after collagenase injection for 3 h under conscious conditions. Nicardipine intravenously at 0.1, 1 and 10 microg kg(-1) min(-1) affected neither haematoma size nor the degree of brain oedema. Nicardipine at these doses provided a stable and dose-dependent decrease in mean blood pressure of 6%, 13% and 33%, respectively, with an increase in heart rate that was apparently caused reflexively. Further, nicardipine did not aggravate the neurological deficits in these intracerebral haemorrhage rats, primarily forearm flexion behaviour on suspension by the tail and circling behaviour. These results indicate that nicardipine infusion stably decreased blood pressure without affecting intracerebral haemorrhage in an intracerebral haemorrhage model in rats.

RISQUE CHIMIQUE DANS LE BATIMENT. Premiere session : Actualites

The present study was designed to examine the correlations between behavioural and oxidative parameters in a quinolinic acid model of Huntington’s disease in rats. The protective effect of melatonin against the excitotoxicity induced by quinolinic acid was investigated. Rats were pre-treated with melatonin (5 or 20 mg/kg) before injection of quinolinic acid (240 nmol/site; 1 μl) into their right corpora striata. The locomotor and exploratory activities as well as the circling behaviour were recorded. The elevated body swing test was also performed. After behavioural experiments, biochemical determinations were carried out. Melatonin partially protected against the increase of circling behaviour caused by quinolinic acid injection. No alteration was found in the number of crossings and rearings of animals treated with melatonin and/or quinolinic acid. Melatonin decreased the percentage of contralateral biased swings induced by quinolinic acid. Melatonin protected against the increase in reactive species and protein carbonyl levels as well as the inhibition of superoxide dismutase activity resulting from quinolinic acid injection. Melatonin was partially effective against the inhibition of striatal catalase activity and a decrease of non-protein thiol levels induced by quinolinic acid. Melatonin was not effective against the inhibition of Na+, K+ ATPase activity caused by quinolinic acid injection. There were significant correlations between circling behaviour and oxidative parameters. The antioxidant property of melatonin is involved, at least in part, in its neuroprotective effect. The results reinforce the idea that melatonin could be useful in overwhelming neurotoxicity caused by quinolinic acid, a rat model of Huntington’s disease.

Homozygosity Mapping Reveals Mutations of GRXCR1 as a Cause of Autosomal-Recessive Nonsyndromic Hearing Impairment

We identified overlapping homozygous regions within the DFNB25 locus in two Dutch and ten Pakistani families with sensorineural autosomal-recessive nonsyndromic hearing impairment (arNSHI). Only one of the families, W98-053, was not consanguineous, and its sibship pointed toward a reduced critical region of 0.9 Mb. This region contained the GRXCR1 gene, and the orthologous mouse gene was described to be mutated in the pirouette (pi) mutant with resulting hearing loss and circling behavior. Sequence analysis of the GRXCR1 gene in hearing-impaired family members revealed splice-site mutations in two Dutch families and a missense and nonsense mutation, respectively, in two Pakistani families. The splice-site mutations are predicted to cause frameshifts and premature stop codons. In family W98-053, this could be confirmed by cDNA analysis. GRXCR1 is predicted to contain a GRX-like domain. GRX domains are involved in reversible S-glutathionylation of proteins and thereby in the modulation of activity and/or localization of these proteins. The missense mutation is located in this domain, whereas the nonsense and splice-site mutations may result in complete or partial absence of the GRX-like domain or of the complete protein. Hearing loss in patients with GRXCR1 mutations is congenital and is moderate to profound. Progression of the hearing loss was observed in family W98-053. Vestibular dysfunction was observed in some but not all affected individuals. Quantitative analysis of GRXCR1 transcripts in fetal and adult human tissues revealed a preferential expression of the gene in fetal cochlea, which may explain the nonsyndromic nature of the hearing impairment.

Circling behavior developed in Dmp1 null mice is due to bone defects in the vestibular apparatus

With age, there is a progressive loss of body balance function. Yet, the potential influence of osteoporosis on body balance is largely unknown. Dentin matrix protein 1 (DMP1) is highly expressed in bone and required for phosphate homeostasis and mineralization. Dmp1 null mice display striking defects in bone structure. In this study we reported circling behavior and hyper reaction to touching in Dmp1 null mice. Our histology, tartrate resistant acid phosphatase (TRAP) staining and µCT data showed dramatic changes, such as an expansion of poorly mineralized matrices, in the Dmp1 null porous bony structure in the vestibular apparatus. The targeted re-expression of DMP1 in the Dmp1 null bone fully rescued not only the bone phenotype, but also circling behavior and hyper reaction. Furthermore, X-gal stain and DMP1 immunohistochemistry assay showed that DMP1 was not expressed in neuron cells or balance related cells in the inner ear, suggesting that a defect in the bony labyrinth of the internal ear is indirectly responsible for the circling behavior and/or hyper reaction to touching. Finally, discovery of DMP1 lacZ signal in pericyte-like cells may suggest a new function of DMP1 in angiogenesis.

Constitutive Activity of the Human TRPML2 Channel Induces Cell Degeneration

The mucolipin (TRPML) ion channel proteins represent a distinct subfamily of channel proteins within the transient receptor potential (TRP) superfamily of cation channels. Mucolipin 1, 2, and 3 (TRPML1, -2, and -3, respectively) are channel proteins that share high sequence homology with each other and homology in the transmembrane domain with other TRPs. Mutations in the TRPML1 protein are implicated in mucolipidosis type IV, whereas mutations in TRPML3 are found in the varitint-waddler mouse. The properties of the wild type TRPML2 channel are not well known. Here we show functional expression of the wild type human TRPML2 channel (h-TRPML2). The channel is functional at the plasma membrane and characterized by a significant inward rectification similar to other constitutively active TRPML mutant isoforms. The h-TRPML2 channel displays nonselective cation permeability, which is Ca(2+)-permeable and inhibited by low extracytosolic pH but not Ca(2+) regulated. In addition, constitutively active h-TRPML2 leads to cell death by causing Ca(2+) overload. Furthermore, we demonstrate by functional mutation analysis that h-TRPML2 shares similar characteristics and structural similarities with other TRPML channels that regulate the channel in a similar manner. Hence, in addition to overall structure, all three TRPML channels also share common modes of regulation.

Phenotypic and Expression Analysis of a Novel Spontaneous Myosin VI Null Mutant Mouse

In humans, hearing is a major factor in quality of life. Mouse models are important tools for the discovery of genes responsible for genetic hearing loss, often enabling analysis of the processes that regulate the onset of deafness in humans. Thus far, at least 400 deafness mutants have been discovered in laboratory mouse populations and used in the study of deafness. Here we report the discovery of a new spontaneous recessive Rinshoken shaker/waltzer (rsv) mutant derived from our in-house C57BL/6J stock, which exhibits circling and/or head-tossing behaviour and complete lack of auditory brain response to any sound pressure. The hearing and balance phenotypes are associated with structural defects, in particular, disorganisation and fusion of stereocilia in the inner ear hair cells. Two sets of intersubspecific N(2) mice were generated for the positional cloning of the rsv mutation. The mutant locus was mapped to a 4.8-Mb region of chromosome 9, which contains myosin VI (Myo6), a gene responsible for deafness in humans and Snell's waltzer mutation in mice. The rsv mutant showed reduced expressions of Myo6 mRNA and MYO6 protein in the inner ear. Moreover, no immunoreactivity was observed in the cochlear and vestibular hair cells in the rsv mutant mice. We sequenced the genomic region (30,154 bp) of Myo6, including all coding exons, a non-coding exon, UTRs and the Myo6 promoter; however, no mutation was discovered in these regions. We therefore speculate that loss of MYO6 expression might cause shaker/waltzer behaviour and deafness in the rsv mutant; also, loss of MYO6 expression might be the result of mutations in an unidentified regulatory region(s) of the gene.

Passive rotation‐induced theta rhythm and orientation homeostasis response

Rhythmic oscillatory activities at the theta frequency (3-12 Hz) have long attracted attention, as they have been implicated in diverse brain functions. There are two kinds of hippocampal theta rhythms: Type 1 is an atropine-resistant noncholinergic theta rhythm, and Type 2 is an atropine-sensitive cholinergic theta rhythm. However, it has not yet been determined whether the theta rhythm generated during passive whole-body rotation is of Type 1 or 2. To clarify this issue, we investigated passive whole-body rotation-induced theta rhythm using C57BL/6J normal and atropine-treated mice. The results demonstrated that atropine [50 mg/kg, intraperitoneally (i.p.)], a cholinergic antagonist, abolished the theta rhythm generated during passive whole-body rotation. Therefore, the passive whole-body rotation-induced theta rhythm is an atropine-sensitive Type 2 theta rhythm. In addition, we found that blocking cholinergic receptors using atropine resulted in the loss of the orientation homeostasis response, which is a circling behavior in the direction opposite to that of the rotating circular treadmill that is generated to maintain a constant orientation. These results suggest that atropine-sensitive Type 2 theta rhythm can be generated by a passive rotation-induced vestibular sensory signal and may be necessary for spatial orientation homeostasis response behavior.

Noradrenergic lesion of the locus coeruleus increases apomorphine-induced circling behavior and the firing activity of substantia nigra pars reticulata neurons in a rat model of Parkinson's disease

The role of noradrenergic depletion of the locus coeruleus (LC) in the pathophysiology of Parkinson's disease (PD) is still unclear. In the present study, apomorphine-induced circling behavior and extracellular firing activity of substantia nigra pars reticulata (SNr) neurons were examined in rats with unilateral 6-hydroxydopamine lesions of the LC, substantia nigra pars compacta (SNc) and with combined SNc and LC lesions. A moderate contralateral circling was observed in rats with LC lesions after apomorphine. Moreover, the circling behavior was obviously increased by further lesions of LC in SNc-lesioned rats. Extracellular recordings indicated that the firing rate of SNr neurons increased significantly and the firing pattern of these neurons also changed towards more irregular and bursty after SNc lesioning as compared to sham-lesioned rats, while the firing rate and pattern were unaffected in rats with simple lesions of the LC. However, the firing rate of SNr neurons in rats with combined LC and SNc lesions increased significantly when compared to that of rats with simple lesions of the SNc, although the firing pattern was not altered. Furthermore, SNc lesions in rats increased the firing rate of SNr neurons with irregular firing pattern, and additional LC lesions in SNc-lesioned rats increased the firing rate of SNr neurons with regular and irregular firing pattern. These results indicate that lesions of the LC intensify apomorphine-induced circling behavior and lead to a further hyperactivity of SNr neurons in a rat model of PD, suggesting that LC-noradrenergic system is involved in the motor dysfunction of PD.

Antioxidant strategy to rescue synaptosomes from oxidative damage and energy failure in neurotoxic models in rats: protective role of S-allylcysteine

The functional preservation of nerve endings since the early stages of toxicity in a given damaging insult-either acute or chronic-by means of antioxidant and neuroprotective agents is a primary need to design therapeutic strategies for neurodegenerative disorders, with particular emphasis on those diseases with excitotoxic and depleted energy metabolism components. S-allylcysteine (SAC), a well-known antioxidant agent, was tested as a post-treatment in different in vitro and in vivo neurotoxic models. Quinolinic acid (QUIN) was used as a typical excitotoxic/pro-oxidant inducer, 3-nitropropionic acid (3-NP) was employed as a mitochondrial function inhibitor, and their combination (QUIN + 3-NP) was also evaluated in in vitro studies. For in vitro purposes, increasing concentrations of SAC (10-100 microM) were added to isolated brain synaptosomes at different times (1, 3 and 6 h) after the incubation with toxins (100 microM QUIN, 1 mM 3-NP or the combination of QUIN (21 microM) + 3-NP (166 microM). Thirty minutes later, lipid peroxidation (LP) and mitochondrial dysfunction (MD) were evaluated. For in vivo studies, SAC (100 mg/kg, i.p.) was given to QUIN- or 3-NP-striatally lesioned rats for 7 consecutive days (starting 120 min post-lesion). LP and MD were evaluated 7 days post-lesion in isolated striatal synaptosomes. Circling behavior was also assessed. Our results describe a differential pattern of protection achieved by SAC, mostly expressed in the 3-NP toxic model, in which nerve ending protection was found within the first hours (1 and 3) after the toxic insult started, supporting the concept that the ongoing oxidative damage and energy depletion can be treated during the first stages of neurotoxic events.

Síndrome vestibular em tamanduá-bandeira (Myrmecophaga tridactyla)

The vestibular syndrome is a well-defined disease in domestic animals but little known in wild ones. Here this affection of central origin is described in a caquetic adult female giant anteater (Myrmecophaga tridactyla), which presented circling behavior, extensor hypermetry in thoracic limbs, head tilt and spontaneous horizontal and positional vertical nystagmus. The animal received tube feeding twice daily and dexamethasone was given subcutaneous once daily at the dosis of 6mg/kg, with a progressive improvement of health after the second day of treatment. Dose was reduced to a half from fourth to sixth day, and to a quarter on seventh day, when the animal died. On the fifth day, however, circle deambulation had ceased and hypermetry, head tilt and nystagmus were reduced. Treating vestibular syndrome is a challenge in wild animal practice. Treatment is affected by hyporexia and anorexia, making difficult the animals´ health improvement, which generally present muscle atrophy.

NAD(P)H oxidase contributes to neurotoxicity in an excitotoxic/prooxidant model of Huntington's disease in rats: Protective role of apocynin

Intrastriatal injection of quinolinic acid (QUIN) to rodents reproduces some biochemical, morphological, and behavioral characteristics of Huntington's disease. NAD(P)H oxidase is an enzymatic complex that catalyzes superoxide anion (O(2).(-)) production from O(2) and NADPH. The present study evaluated the role of NAD(P)H oxidase in the striatal damage induced by QUIN (240 nmol/microl) in adult male Wistar rats by means of apocynin (APO; 5 mg/kg i.p.), a specific NAD(P)H oxidase inhibitor. Rats were given APO 30 min before and 1 hr after QUIN injection or only 30 min after QUIN injection. NAD(P)H oxidase activity was measured in striatal homogenates by O2(*)(-) production. QUIN infusion to rats significantly increased striatal NAD(P)H oxidase activity (2 hr postlesion), whereas APO treatments decreased the QUIN-induced enzyme activity (2 hr postlesion), lipid peroxidation (3 hr postlesion), circling behavior (6 days postlesion), and histological damage (7 days postlesion). The addition of NADH to striatal homogenates increased NAD(P)H oxidase activity in striata from QUIN-treated animals but not from sham rats. Interestingly, O2(*)(-) production in QUIN-lesioned striata was unaffected by the addition of substrates for intramitochondrial O2(*)(-) production, xanthine oxidase and nitric oxide synthase, suggesting that NAD(P)H oxidase may be the main source of O2(*)(-) in QUIN-treated rats. Moreover, the administration of MK-801 to rats as a pretreatment resulted in a complete prevention of the QUIN-induced NAD(P)H activation, suggesting that this toxic event is completely dependent on N-methyl-D-aspartate receptor overactivation. Our results also suggest that NAD(P)H oxidase is involved in the pathogenic events linked to excitotoxic/prooxidant conditions.

CLRN1 Is Nonessential in the Mouse Retina but Is Required for Cochlear Hair Cell Development

Mutations in the CLRN1 gene cause Usher syndrome type 3 (USH3), a human disease characterized by progressive blindness and deafness. Clarin 1, the protein product of CLRN1, is a four-transmembrane protein predicted to be associated with ribbon synapses of photoreceptors and cochlear hair cells, and recently demonstrated to be associated with the cytoskeleton. To study Clrn1, we created a Clrn1 knockout (KO) mouse and characterized the histological and functional consequences of Clrn1 deletion in the retina and cochlea. Clrn1 KO mice do not develop a retinal degeneration phenotype, but exhibit progressive loss of sensory hair cells in the cochlea and deterioration of the organ of Corti by 4 months. Hair cell stereocilia in KO animals were longer and disorganized by 4 months, and some Clrn1 KO mice exhibited circling behavior by 5–6 months of age. Clrn1 mRNA expression was localized in the retina using in situ hybridization (ISH), laser capture microdissection (LCM), and RT–PCR. Retinal Clrn1 transcripts were found throughout development and adulthood by RT–PCR, although expression peaked at P7 and declined to undetectable levels in adult retina by ISH. LCM localized Clrn1 transcripts to the retinas inner nuclear layer, and WT levels of retinal Clrn1 expression were observed in photoreceptor-less retinas. Examination of Clrn1 KO mice suggests that CLRN1 is unnecessary in the murine retina but essential for normal cochlear development and function. This may reflect a redundancy in the mouse retina not present in human retina. In contrast to mouse KO models of USH1 and USH2, our data indicate that Clrn1 expression in the retina is restricted to the Müller glia. This is a novel finding, as most retinal degeneration associated proteins are expressed in photoreceptors, not in glia. If CLRN1 expression in humans is comparable to the expression pattern observed in mice, this is the first report of an inner retinal protein that, when mutated, causes retinal degeneration.

Grafted neural stem cells migrate to substantia nigra and improve behavior in Parkinsonian rats

Neural stem cell (NSC) transplantation has the potential to treat neurodegenerative diseases such as Parkinson's disease (PD). In this study, we investigated the effect of transplanted NSCs in a PD animal model. NSCs isolated from the subventricular zone (SVZ) of E14 rats were cultured in vitro to produce neurospheres, which were subsequently infected with recombinant adeno-associated virus (rAAV2) expressing enhanced green fluorescent protein (EGFP). The PD animal model was established by unilateral injection of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle (MFB) of Sprague–Dawley rats. Once the model was established, EGFP-expressing NSCs were transplanted into the substantia nigra pars compacta (SNc) or striatum of PD rats. We found that NSCs transplanted into either site significantly reduced apomorphine-induced circling behavior of PD rats. Pathological analysis revealed that the EGFP-expressing NSCs could be detected at both injection sites at 1, 2 and 4 months after transplantation. SNc transplanted cells dispersed within the SNc with a significant portion differentiated into tyrosine hydroxylase-positive neurons. Whereas cells transplanted into the striatum migrated ventrally and posteriorly towards the SNc. These results suggest that the 6-OHDA damaged brain area attracts grafted NSCs, which migrated from the striatum and survived for a long time in SNc, resulting in behavioral improvement of PD rats.

Long term exposure to the chemokine CCL2 activates the nigrostriatal dopamine system: a novel mechanism for the control of dopamine release

Accumulating evidence show that chemokines can modulate the activity of neurons through various mechanisms. Recently, we demonstrated that CCR2, the main receptor for the chemokine CCL2, is constitutively expressed in dopamine neurons in the rat substantia nigra. Here we show that unilateral intranigral injections of CCL2 (50 ng) in freely moving rats increase extracellular concentrations of dopamine and its metabolites and decrease dopamine content in the ipsilateral dorsal striatum. Furthermore, these CCL2 injections are responsible for an increase in locomotor activity resulting in contralateral circling behavior. Using patch-clamp recordings of dopaminergic neurons in slices of the rat substantia nigra, we observed that a prolonged exposure (>8 min) to 10 nM CCL2 significantly increases the membrane resistance of dopaminergic neurons by closure of background channels mainly selective to potassium ions. This leads to an enhancement of dopaminergic neuron discharge in pacemaker or burst mode necessary for dopamine release. We provide here the first evidence that application of CCL2 on dopaminergic neurons increases their excitability, dopamine release and related locomotor activity.

Life and Death of Sensory Hair Cells Expressing Constitutively Active TRPML3

The varitint-waddler mutation A419P renders TRPML3 constitutively active, resulting in cationic overload, particularly in sustained influx of Ca(2+). TRPML3 is expressed by inner ear sensory hair cells, and we were intrigued by the fact that hair cells are able to cope with expressing the TRPML3(A419P) isoform for weeks before they ultimately die. We hypothesized that the survival of varitint-waddler hair cells is linked to their ability to deal with Ca(2+) loads due to the abundance of plasma membrane calcium ATPases (PMCAs). Here, we show that PMCA2 significantly reduced [Ca(2+)](i) increase and apoptosis in HEK293 cells expressing TRPML3(A419P). The deaf-waddler isoform of PMCA2, operating at 30% efficacy, showed a significantly decreased ability to rescue the Ca(2+) loading of cells expressing TRPML3(A419P). When we combined mice heterozygous for the varitint-waddler mutant allele with mice heterozygous for the deaf-waddler mutant allele, we found severe hair bundle defects as well as increased hair cell loss compared with mice heterozygous for each mutant allele alone. Furthermore, 3-week-old double mutant mice lacked auditory brainstem responses, which were present in their respective littermates containing single mutant alleles. Likewise, heterozygous double mutant mice exhibited severe circling behavior, which was not observed in mice heterozygous for TRPML3(A419P) or PMCA2(G283S) alone. Our results provide a molecular rationale for the delayed hair cell loss in varitint-waddler mice. They also show that hair cells are able to survive for weeks with sustained Ca(2+) loading, which implies that Ca(2+) loading is an unlikely primary cause of hair cell death in ototoxic stress situations.

Vestibular Critical Period, Maturation of Central Vestibular Neurons, and Locomotor Control

Mutant mice are a good model to study to what extent the postnatal activity of sensory afferents is necessary for the maturation of central neurons. In particular, the question arises whether the signals carried by the first-order vestibular neurons, which encode information on the head movement of pups, are necessary for the maturation of second-order vestibular neurons. To address that question, juvenile and adult transgenic, vestibular-deficient mutants where a null mutation of the KCNE1 potassium-channel gene leads to degeneration of all hair cells of the inner ear just after birth were studied. These KCNE1(-/-) mutants are deaf and show quasi-constant head bobbing and a permanent shaker/waltzer phenotype. This behavior is not due to persistent abnormalities of the membrane properties of central vestibular neurons, because their maturation is delayed but not impaired by the absence of sensory vestibular information. On the other hand, the data shed light on how the membrane properties of vestibular neurons might be modified according to functional requirements or following lesions. The expression levels of the protein calretinin that regulates the intracellular free-calcium concentration in central vestibular neurons could play a major role both in intact animals and following labyrinthectomy. By comparing the KCNE1(-/-) mutant mice to other vestibular-deficient animals, it was concluded that the suppression of vestibular inputs during a "critical period" of postnatal development can induce a permanent circling behavior, but that this phenotype is not always due to congenital vestibular deficiency.

Growth deficits in a postnatal day 3 rat model of hypoxic-ischemic brain injury

The postnatal day (P) 3 rat model of hypoxic-ischemic (HI) brain injury provides valuable information regarding the cellular response to HI injury in a very immature brain. Our present study is the first to examine growth, metabolic, and behavioral outcomes following a P3 HI brain injury. Rats were injured by cauterizing the right common carotid, and exposure to 8% oxygen for 1.5 h. Control rats received sham surgery and exposure to 1.5 h of room air. One cohort of rats was examined for growth patterns through P33, evaluated using a battery of tests focused on early postnatal feeding behaviors, and studied using the open field paradigm during the early postnatal and postweaning periods. Another cohort of rats was used to examine metabolic parameters using indirect calorimetry. Significant growth deficits emerged in injured rats during the second postnatal week. No significant differences between groups were noted in the expression of feeding-related behaviors or in metabolic parameters between groups. However, we did observe significant associations between feeding-related behaviors and P14 growth parameters in injured rats. In the open field assessment, HI rats showed increased circling and supination behaviors only during the early postnatal period. Our data reveal that P3 HI brain injury results in generalized growth deficits that persist through postweaning. Analyses suggest that alterations in feeding-related behaviors contribute to growth deficits following a P3 HI brain injury.

CLIC5 is required for appropriate thermogenesis during fasting

CLIC5 (Chloride Intracellular Channel 5) is an intracellular protein that has been shown to associate with the actin cytoskeleton of placental microvilli and plays a role in the maintenance of hair cell stereocilia in the inner ear. Mice that are homozygous for the mutant allele of Clic5, designated jbg, exhibit hyperactivity and circling behavior. In these studies we show that the jbg/jbg mice have an impaired ability to regulate appropriate thermogenesis during fasting. Although their basal core body temperatures and surface temperatures are not different from wild type mice, during prolonged food restriction the mutant mice become severely hypothermic. Furthermore, the mutant mice lose a greater percentage of their body weight, and tend to exhibit vasodilation and piloerection during fasting. Although their stomach morphology and gastric acid secretion are normal under basal conditions, the jbg/jbg mice also experience gastric hemorrhaging, the rate and severity of which increase with the duration of fasting. These hemorrhages are completely reversible when food is replaced. These data suggest a role for CLIC5 in the maintenance of body temperature during fasting, either by directly influencing non‐shivering thermogenesis or by affecting energy metabolism.