Increased elasticity of sucrose demand during hyperdopaminergic states in rats.

RATIONALE: Deficits in cost-benefit decision-making are a core feature of several psychiatric disorders, including substance addiction, eating disorders and bipolar disorder. Mesocorticolimbic dopamine signalling has been implicated in various processes related to cognition and reward, but its precise role in reward valuation and cost-benefit trade-off decisions remains incompletely understood. OBJECTIVES: We assessed the role of mesocorticolimbic dopamine signalling in the relationship between price and consumption of sucrose, to better understand its role in cost-benefit decisions. METHODS: Dopamine neurons in the ventral tegmental area (VTA) were chemogenetically activated in rats, and a behavioural economics approach was used to quantify the relationship between price and consumption of sucrose. Motivation for sucrose was also assessed under a progressive ratio (PR) schedule of reinforcement. To further gauge the role of dopamine in cost-benefit trade-offs for sucrose, the effects of treatment with D-amphetamine and the dopamine receptor antagonist alpha-flupentixol were assessed. RESULTS: Chemogenetic activation of VTA dopamine neurons increased demand elasticity, while responding for sucrose under a PR schedule of reinforcement was augmented upon stimulation of VTA dopamine neurons. Treatment with amphetamine partially replicated the effects of chemogenetic dopamine neuron activation, whereas treatment with alpha-flupentixol reduced free consumption of sucrose and had mixed effects on demand elasticity. CONCLUSIONS: Stimulation of mesocorticolimbic dopaminergic neurotransmission altered cost-benefit trade-offs in a complex manner. It reduced the essential value of palatable food, increased incentive motivation and left free consumption unaltered. Together, these findings imply that mesocorticolimbic dopamine signalling differentially influences distinct components of cost expenditure processes aimed at obtaining rewards.

On the interrelation between alcohol addiction-like behaviors in rats.

RATIONALE: Alcohol use disorder (AUD) is a complex, heterogeneous disorder that only occurs in a minority of alcohol users. Various behavioral constructs, including excessive intake, habit formation, motivation for alcohol and resistance to punishment have been implicated in AUD, but their interrelatedness is unclear. OBJECTIVE: The aim of this study was therefore to explore the relation between these AUD-associated behavioral constructs in rats. We hypothesised that a subpopulation of animals could be identified that, based on these measures, display consistent AUD-like behavior. METHODS: Lister Hooded rats (n = 47) were characterised for alcohol consumption, habit formation, motivation for alcohol and quinine-adulterated alcohol consumption. The interrelation between these measures was evaluated through correlation and cluster analyses. In addition, addiction severity scores were computed using different combinations of the behavioral measures, to assess the consistency of the AUD-like subpopulation. RESULTS: We found that the data was uniformly distributed, as there was no significant tendency of the behavioral measures to cluster in the dataset. On the basis of multiple ranked addiction severity scores, five animals (~ 11%) were classified as displaying AUD-like behavior. The composition of the remaining subpopulation of animals with the highest addiction severity score (9 rats; ~ 19%) varied, depending on the combination of measures included. CONCLUSION: Consistent AUD-like behavior was detected in a small proportion of alcohol drinking rats. Alcohol consumption, habit formation, motivation for alcohol and punishment resistance contribute in varying degrees to the AUD-like phenotype across the population. These findings emphasise the importance of considering the heterogeneity of AUD-like behavior.

Cue and Reward Evoked Dopamine Activity Is Necessary for Maintaining Learned Pavlovian Associations.

Associating natural rewards with predictive environmental cues is crucial for survival. Dopamine (DA) neurons of the ventral tegmental area (VTA) are thought to play a crucial role in this process by encoding reward prediction errors (RPEs) that have been hypothesized to play a role in associative learning. However, it is unclear whether this signal is still necessary after animals have acquired a cue-reward association. In order to investigate this, we trained mice to learn a Pavlovian cue-reward association. After learning, mice show robust anticipatory and consummatory licking behavior. As expected, calcium activity of VTA DA neurons goes up for cue presentation as well as reward delivery. Optogenetic inhibition during the moment of reward delivery disrupts learned behavior, even in the continued presence of reward. This effect is more pronounced over trials and persists on the next training day. Moreover, outside of the task licking behavior and locomotion are unaffected. Similarly to inhibitions during the reward period, we find that inhibiting cue-induced dopamine (DA) signals robustly decreases learned licking behavior, indicating that cue-related DA signals are a potent driver for learned behavior. Overall, we show that inhibition of either of these DA signals directly impairs the expression of learned associative behavior. Thus, continued DA signaling in a learned state is necessary for consolidating Pavlovian associations.SIGNIFICANCE STATEMENT Dopamine (DA) neurons of the ventral tegmental area (VTA) have long been suggested to be necessary for animals to associate environmental cues with rewards that they predict. Here, we use time-locked optogenetic inhibition of these neurons to show that the activity of these neurons is directly necessary for performance on a Pavlovian conditioning task, without affecting locomotor per se These findings provide further support for the direct importance of second-by-second DA neuron activity in associative learning.

Baclofen and naltrexone, but not N-acetylcysteine, affect voluntary alcohol drinking in rats regardless of individual levels of alcohol intake.

In humans, there is profound individual variation in the risk of alcohol use disorder (AUD). Because GABA, opioid and glutamate neurotransmission have been implicated in AUD, functional differences in these neural systems may underlie the individual vulnerability to AUD. We therefore determined the effects of drugs affecting GABA, opioid and glutamatergic neurotransmission on alcohol consumption in rats that differed in baseline alcohol intake. Subgroups of low-, medium- and high-alcohol-drinking rats were selected on the basis of alcohol consumption using an intermittent alcohol access procedure. The subgroups were treated with the GABAB receptor agonist baclofen, the opioid receptor antagonist naltrexone and the cysteine precursor N-acetylcysteine, and the effects on alcohol intake and preference were determined. Both baclofen and naltrexone reduced alcohol consumption, but N-acetylcysteine did not. These effects were comparable for low-, medium- and high-alcohol-drinking rats. However, there was a substantial degree of individual variation in the responsivity to baclofen and naltrexone, across the subgroups. Taken together, these results suggest that variation in alcohol consumption does not predict the responsivity to baclofen and naltrexone. This implies that individual variability in alcohol consumption on the one hand and sensitivity to treatment with these drugs on the other hand represent separate processes that likely involve distinct biological mechanisms.

Stage-specific functions of Semaphorin7A during adult hippocampal neurogenesis rely on distinct receptors.

The guidance protein Semaphorin7A (Sema7A) is required for the proper development of the immune and nervous systems. Despite strong expression in the mature brain, the role of Sema7A in the adult remains poorly defined. Here we show that Sema7A utilizes different cell surface receptors to control the proliferation and differentiation of neural progenitors in the adult hippocampal dentate gyrus (DG), one of the select regions of the mature brain where neurogenesis occurs. PlexinC1 is selectively expressed in early neural progenitors in the adult mouse DG and mediates the inhibitory effects of Sema7A on progenitor proliferation. Subsequently, during differentiation of adult-born DG granule cells, Sema7A promotes dendrite growth, complexity and spine development through ß1-subunit-containing integrin receptors. Our data identify Sema7A as a key regulator of adult hippocampal neurogenesis, providing an example of how differential receptor usage spatiotemporally controls and diversifies the effects of guidance cues in the adult brain.

Effects of neonatal exposure to the flame retardant tetrabromobisphenol-A, aluminum diethylphosphinate or zinc stannate on long-term potentiation and synaptic protein levels in mice.

Brominated flame retardants such as tetrabromobisphenol-A (TBBPA) may exert (developmental) neurotoxic effects. However, data on (neuro)toxicity of halogen-free flame retardants (HFFRs) are scarce. Recent in vitro studies indicated a high neurotoxic potential for some HFFRs, e.g., zinc stannate (ZS), whereas the neurotoxic potential of other HFFRs, such as aluminum diethylphosphinate (Alpi), appears low. However, the in vivo (neuro)toxicity of these compounds is largely unknown. We therefore investigated effects of neonatal exposure to TBBPA, Alpi or ZS on synaptic plasticity in mouse hippocampus. Male C57bl/6 mice received a single oral dose of 211 µmol/kg bw TBBPA, Alpi or ZS on postnatal day (PND) 10. On PND 17-19, effects on hippocampal synaptic plasticity were investigated using ex vivo extracellular field recordings. Additionally, we measured levels of postsynaptic proteins involved in long-term potentiation (LTP) as well as flame retardant concentrations in brain, muscle and liver tissues. All three flame retardants induced minor, but insignificant, effects on LTP. Additionally, TBBPA induced a minor decrease in post-tetanic potentiation. Despite these minor effects, expression of selected synaptic proteins involved in LTP was not affected. The flame retardants could not be measured in significant amounts in the brains, suggesting low bioavailability and/or rapid elimination/metabolism. We therefore conclude that a single neonatal exposure on PND 10 to TBBPA, Alpi or ZS does affect neurodevelopment and synaptic plasticity only to a small extent in mice. Additional data, in particular on persistence, bioaccumulation and (in vivo) toxicity, following prolonged (developmental) exposure are required for further (human) risk assessment.

Physiological challenges for intracortical electrodes.

The clinical use of chronic electrode implants for measurement or stimulation of neuronal activity has increased over the past decade with the advent of deep brain stimulation and the use of brain-computer interfaces. However, despite the wide-spread application of electrode implants, their chronic use is still limited by technical difficulties. Many of the reported issues, ranging from short-circuits to loss of signal due to increased electrical impedance, may be traced back to the reaction of the cortical tissue to the implanted devices: the foreign body response (FBR). This response consists of several phases that ultimately result in neuronal loss and the formation of a dense glial sheath that encapsulates the implant. Empirical evidence suggests that reducing the FBR has a positive effect on the electrical properties of implants, which can potentially expand their clinical use by improving their chronic usability. The primary focus of this work is to review the consequences of the FBR and recent developments that can be considered to control and limit its development. We will discuss how the choice of device material and electrode-architecture influences the tissue reaction, as well as modifications that allow for less stiff implants, increase electrode conductivity, or improve the implant-tissue integration. Several promising biological solutions include the local release of anti-inflammatory compounds to weaken the initial inflammatory phase of the FBR, as well as methods to diminish the negative effects of the glial sheath on neuronal regrowth.

Identification of Srp9 as a febrile seizure susceptibility gene.

OBJECTIVE: Febrile seizures (FS) are the most common seizure type in young children. Complex FS are a risk factor for mesial temporal lobe epilepsy (mTLE). To identify new FS susceptibility genes we used a forward genetic strategy in mice and subsequently analyzed candidate genes in humans. METHODS: We mapped a quantitative trait locus (QTL1) for hyperthermia-induced FS on mouse chromosome 1, containing the signal recognition particle 9 (Srp9) gene. Effects of differential Srp9 expression were assessed in vivo and in vitro. Hippocampal SRP9 expression and genetic association were analyzed in FS and mTLE patients. RESULTS: Srp9 was differentially expressed between parental strains C57BL/6J and A/J. Chromosome substitution strain 1 (CSS1) mice exhibited lower FS susceptibility and Srp9 expression than C57BL/6J mice. In vivo knockdown of brain Srp9 reduced FS susceptibility. Mice with reduced Srp9 expression and FS susceptibility, exhibited reduced hippocampal AMPA and NMDA currents. Downregulation of neuronal Srp9 reduced surface expression of AMPA receptor subunit GluA1. mTLE patients with antecedent FS had higher SRP9 expression than patients without. SRP9 promoter SNP rs12403575(G/A) was genetically associated with FS and mTLE. INTERPRETATION: Our findings identify SRP9 as a novel FS susceptibility gene and indicate that SRP9 conveys its effects through endoplasmic reticulum (ER)-dependent synthesis and trafficking of membrane proteins, such as glutamate receptors. Discovery of this new FS gene and mechanism may provide new leads for early diagnosis and treatment of children with complex FS at risk for mTLE.

Repeated agouti related peptide (83-132) injections inhibit cocaine-induced locomotor sensitisation, but not via the nucleus accumbens.

Drug addiction is a chronic relapsing brain disease for which many of the underlying neuronal mechanisms are yet to be unravelled. There seems to be an interaction between the melanocortin system and drugs of abuse. For instance, infusion of the melanocortin MC4 receptor antagonist SHU9119 (Ac-Nle-cyclo(-Asp-His-D-2-Nal-Arg-Trp-Lys)-NH2) into the nucleus accumbens results in conditioned place avoidance, reduces the amount of lever presses for cocaine and blocks development of cocaine-induced locomotor sensitisation. The aim of this study is to determine whether the induction of locomotor sensitisation to repeated cocaine is inhibited by the melanocortin MC4 receptor inverse agonist Agouti Related Peptide (AgRP83-132). Rats were sensitised to daily cocaine injections for 5 consecutive days and 30 min prior to every daily cocaine injection, rats received an intracerebroventricular (i.c.v.) or intra nucleus accumbens injection with AgRP(83-132) or saline, to determine whether we could inhibit cocaine-induced locomotor sensitisation. We show that i.c.v. injections of AgRP(83-132) inhibit cocaine-induced locomotor sensitisation. This effect is not regulated via the nucleus accumbens, since injecting the melanocortin receptor inverse agonist AgRP(83-132) directly into the nucleus accumbens was unable to inhibit the cocaine-induced locomotor sensitisation. This implicates that the nucleus accumbens is an unlikely site to inhibit the induction of locomotor sensitisation via the melanocortin MC4 receptor. This is in contrast to other studies that show an effect of the melanocortin MC4 receptor antagonist SHU9119 on locomotor sensitisation when injected into the nucleus accumbens.

Hyperinsulinemia in rats causes impairment of spatial memory and learning with defects in hippocampal synaptic plasticity by involvement of postsynaptic mechanisms.

In addition to its peripheral metabolic functions, insulin acts as a central neuromodulator and affects synaptic plasticity of the hippocampal neurons. In this study, hyperinsulinemic obese zucker rats (OZR) with autosomal recessive mutation of the fa-gene were tested in water maze for learning and memory. The animals were then decapitated and hippocampal slices were prepared for electrophysiological examination. In the water maze test, the OZR performed less efficient than their counter lean control rats (LCR). The OZR showed prolonged latency and increased distance swam to reach a hidden platform. In the electrophysiological experiments, the hippocampal slices were examined for paired-pulse facilitation (PPF), long-term potentiation (LTP), and depression expression. The results showed that while the PPF (thus mainly the presynaptic mechanisms) was not affected, the LTP expression (169.9 ± 16.6 vs. 310.7 ± 2.4 %) and the synaptic plasticity range (69.2 vs. 211.2 %) were both reduced in the OZR animals compared to the LCR. It is concluded that hyperinsulinemia in the OZR resulted in defects in hippocampal synaptic plasticity associated with deterioration in spatial learning and memory functions.

Semaphorin7A and its receptors: pleiotropic regulators of immune cell function, bone homeostasis, and neural development.

Semaphorins form a large, evolutionary conserved family of cellular guidance signals. The semaphorin family contains several secreted and transmembrane proteins, but only one GPI-anchored member, Semaphorin7A (Sema7A). Although originally identified in immune cells, as CDw108, Sema7A displays widespread expression outside the immune system. It is therefore not surprising that accumulating evidence supports roles for this protein in a wide variety of biological processes in different organ systems and in disease. Well-characterized biological effects of Sema7A include those during bone and immune cell regulation, neuron migration and neurite growth. These effects are mediated by two receptors, plexinC1 and integrins. However, most of what is known today about Sema7A signaling concerns Sema7A-integrin interactions. Here, we review our current knowledge of Sema7A function and signaling in different organ systems, highlighting commonalities between the cellular effects and signaling pathways activated by Sema7A in different cell types. Furthermore, we discuss a potential role for Sema7A in disease and provide directions for further research.

Morphine withdrawal enhances constitutive µ-opioid receptor activity in the ventral tegmental area.

µ-Opioid receptors (MORs) in the ventral tegmental area (VTA) are pivotally involved in addictive behavior. While MORs are typically activated by opioids, they can also become constitutively active in the absence of any agonist. In the current study, we present evidence that MOR constitutive activity is highly relevant in the mouse VTA, as it regulates GABAergic input to dopamine neurons. Specifically, suppression of MOR constitutive activity with the inverse agonist KC-2-009 enhanced GABAergic neurotransmission onto VTA dopamine neurons. This inverse agonistic effect was fully blocked by the specific MOR neutral antagonist CTOP, which had no effect on GABAergic transmission itself. We next show that withdrawal from chronic morphine further increases the magnitude of inverse agonistic effects at the MOR, suggesting enhanced MOR constitutive activity. We demonstrate that this increase can be an adaptive response to the detrimental elevation in cAMP levels known to occur during morphine withdrawal. These findings offer important insights in the physiological occurrence and function of MOR constitutive activity, and have important implications for therapeutic strategies aimed at normalizing MOR signaling during addiction and opioid overdose.

Effect of chronic intracerebroventricular insulin administration in rats on the peripheral glucose metabolism and synaptic plasticity of CA1 hippocampal neurons.

In this study we examined the effects of sustained intracerebroventricular insulin infusion on hippocampal synaptic plasticity in rats. Insulin was infused intracerebroventricularly in male Wistar rats (n=12) for 3 months using osmotic minipumps. A control group (n=12) received a sham operation. Insulin infusion led to an initial reduction in food intake and body weight gain, but these differences attenuated over 12 weeks. Insulin infusion did not affect fasting or non-fasting blood glucose levels. Field synaptic potentials recording from the hippocampus demonstrated a defect in the expression of long-term potentiation. Sharp electrode current-clamp recording showed that CA1 pyramidal cells fire action potentials in response to prolonged depolarizing current injection and those action potentials showed progressive broadening. The action potential broadening in the insulin-perfused animals were significantly longer than the control. The amplitude of slow after hyperpolarization (sAHP) was measured after manually "clamping" the cells at -65 mV and injecting currents to evoke a train of four APs. The sAHP amplitude was significantly longer than in the control animals. We conclude that local insulin infusion into the brain of rats had significant effects on synaptic plasticity in the absence of marked effects on systemic glucose levels. These results indicate that long-term elevation of insulin levels can have adverse effects directly on the brain.

Physiology of repetitive transcranial magnetic stimulation of the human brain.

During the last two decades, transcranial magnetic stimulation (TMS) has rapidly become a valuable method to investigate noninvasively the human brain. In addition, repetitive TMS (rTMS) is able to induce changes in brain activity that last after stimulation. Therefore, rTMS has therapeutic potential in patients with neurologic and psychiatric disorders. It is, however, unclear by which mechanism rTMS induces these lasting effects on the brain. The effects of rTMS are often described as LTD- or LTP-like, because the duration of these alterations seems to implicate changes in synaptic plasticity. In this review we therefore discuss, based on rTMS experiments and knowledge about synaptic plasticity, whether the physiologic basis of rTMS-effects relates to changes in synaptic plasticity. We present seven lines of evidence that strongly suggest a link between the aftereffects induced by rTMS and the induction of synaptic plasticity. It is, nevertheless, important to realize that at present it is impossible to demonstrate a direct link between rTMS on the one hand and synaptic plasticity on the other. Therefore, we provide suggestions for future, innovating research, aiming to investigate both the local effects of rTMS on the synapse and the effects of rTMS on other, more global levels of brain organization. Only in that way can the aftereffects of rTMS on the brain be completely understood.

Long-lasting modulation of synaptic plasticity in rat hippocampus after early-life complex febrile seizures.

A small fraction of children with febrile seizures appears to develop cognitive impairments. Recent studies in a rat model of hyperthermia-induced febrile seizures indicate that prolonged febrile seizures early in life have long-lasting effects on the hippocampus and induce cognitive deficits. However, data on network plasticity and the nature of cognitive deficits are conflicting. We examined three specific measures of hippocampal plasticity in adult rats with a prior history of experimental febrile seizures: (i) activity-dependent synaptic plasticity (long-term potentiation and depression) by electrophysiological recordings of Schaffer collateral/commissural-evoked field excitatory synaptic potentials in CA1 of acute hippocampal slices; (ii) Morris water maze spatial learning and memory; and (iii) hippocampal mossy fiber plasticity by Timm histochemistry and quantification of terminal sprouting in CA3 and the dentate gyrus. We found enhanced hippocampal CA1 long-term potentiation and reduced long-term depression but normal spatial learning and memory in adult rats that were subjected to experimental febrile seizures on postnatal day 10. Furthermore, rats with experimental febrile seizures showed modest but significant sprouting of mossy fiber collaterals into the inner molecular layer of the dentate gyrus in adulthood. We conclude that enhanced CA1 long-term potentiation and mild mossy fiber sprouting occur after experimental febrile seizures, without affecting spatial learning and memory in the Morris water maze. These long-term functional and structural alterations in hippocampal plasticity are likely to play a role in the enhanced seizure susceptibility in this model of prolonged human febrile seizures but do not correlate with overt cognitive deficits.

Announced reward counteracts the effects of chronic social stress on anticipatory behavior and hippocampal synaptic plasticity in rats.

Chronic stress causes insensitivity to rewards (anhedonia) in rats, reflected by the absence of anticipatory behavior for a sucrose-reward, which can be reversed by antidepressant treatment or repeated announced transfer to an enriched cage. It was, however, not clear whether the highly rewarding properties of the enriched cage alone caused this reversal or whether the anticipation of this reward as such had an additional effect. Therefore, the present study compared the consequences of the announcement of a reward to the mere effect of a reward alone with respect to their efficacy to counteract the consequences of chronic stress. Two forms of synaptic plasticity, long-term potentiation and long-term depression were investigated in area CA1 of the hippocampus. This was done in socially stressed rats (induced by defeat and subsequent long-term individual housing), socially stressed rats that received a reward (short-term enriched housing) and socially stressed rats to which this reward was announced by means of a stimulus that was repeatedly paired to the reward. The results were compared to corresponding control rats. We show that announcement of enriched housing appeared to have had an additional effect compared to the enriched housing per se as indicated by a significant higher amount of LTP. In conclusion, announced short-term enriched housing has a high and long-lasting counteracting efficacy on stress-induced alterations of hippocampal synaptic plasticity. This information is important for counteracting the consequences of chronic stress in both human and captive rats.

Alterations in serotonin signalling are involved in the hyperactivity of Pitx3-deficient mice.

Pitx3 deficiency in mice causes a dramatic loss of dopaminergic neurones located in the substantia nigra pars compacta during development. This early disruption of the nigrostriatal pathway in Pitx3-deficient mice is characterized by increased spontaneous home-cage activity levels during the habitual sleep phase of these animals. These findings are reminiscent of the spontaneous hyperactivity in mice neonatally lesioned with 6-hydroxydopamine, which is caused by an extensive serotonergic hyperinnervation of the striatum. The present study investigated whether an imbalance between dopamine (DA) and serotonin (5-HT) signalling is involved in the behavioural phenotype of Pitx3-deficient mice. Serotonergic hyperinnervation was demonstrated by increased [3H]-citalopram autoradiographic binding specifically in the dorsal striatum of adult Pitx3-deficient mice, indicating alterations in 5-HT transporter levels that correlated to DA dysfunction in Pitx3 deficiency. In addition, stimulus-induced release of DA and 5-HT indicated an altered balance between these neurotransmitters in the dorsal striatum of Pitx3-/- mice. To determine whether the increased 5-HT signalling was involved in the spontaneous hyperactivity during the light phase observed in Pitx3 deficiency, we treated Pitx3-deficient and control mice with the selective irreversible tryptophan hydroxylase inhibitor p-chlorophenylalanine to decrease 5-HT levels. Reduction of 5-HT levels in Pitx3-deficient mice decreased their locomotor activity to normal levels, whereas the same treatment increased the locomotor activity levels of control mice. Taken together, our results indicate alterations in 5-HT signalling in Pitx3-deficient mice that underlie their spontaneous hyperactivity.

Phenotypic segregation of aphakia and Pitx3-null mutants reveals that Pitx3 deficiency increases consolidation of specific movement components.

Deficiency of the meso-diencephalic dopamine (mdDA) neuron specific transcription factor Pitx3 in aphakia (ak) mice results in the loss of the substantia nigra compacta (SNc). Concomitantly, reduced spontaneous locomotor behavior, symptoms reminiscent to those in Parkinson's disease, has been reported. However, the ak mouse line originates from the 1960s and has been compared to C57BL/6J inbred controls. Therefore, to define Pitx3 gene function in baseline and novelty-induced locomotor behavior and mdDA neuronal activity, we analyzed Pitx3-deficiency in a controlled genetic and epigenetic background. The analysis implicated that, in contrast to the controversial and previously reported hypo-activity in ak mice, Pitx3-/- mice showed normal dark phase motor activity levels. Our data also revealed that ak and Pitx3-/- mice both display a similar neuro-anatomical and physiological phenotype, and, interestingly, showed increased spontaneous home cage activity levels during their habitual sleep phase. Further behavioral analysis revealed that both ak and Pitx3-/- mice have reduced transitions but increased consolidation of specific locomotor behaviors, such as rearing and horizontal movement. Thus, Pitx3 is not involved in the expression of nighttime motor activity levels, but is critical for selective mdDA neuronal activity and associated with increased consolidation of movement.

Neonatal exposure to brominated flame retardant BDE-47 reduces long-term potentiation and postsynaptic protein levels in mouse hippocampus.

BACKGROUND: Increasing environmental levels of brominated flame retardants raise concern about possible adverse effects, particularly through early developmental exposure. OBJECTIVE: The objective of this research was to investigate neurodevelopmental mechanisms underlying previously observed behavioral impairments observed after neonatal exposure to polybrominated diphenyl ethers (PBDEs). METHODS: C57Bl/6 mice received a single oral dose of 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) on postnatal day (PND) 10 (i.e., during the brain growth spurt). On PND17-19, effects on synaptic plasticity, levels of postsynaptic proteins involved in long-term potentiation (LTP), and vesicular release mechanisms were studied ex vivo. We investigated possible acute in vitro effects of BDE-47 on vesicular catecholamine release and intracellular Ca(2+) in rat pheochromocytoma (PC12) cells. RESULTS: Field-excitatory postsynaptic potential (f-EPSP) recordings in the hippocampal CA1 area demonstrated reduced LTP after exposure to 6.8 mg (14 micromol)/kg body weight (bw) BDE-47, whereas paired-pulse facilitation was not affected. Western blotting of proteins in the postsynaptic, triton-insoluble fraction of hippocampal tissue revealed a reduction of glutamate receptor subunits NR2B and GluR1 and autophosphorylated-active Ca(2+)/calmodulin-dependent protein kinase II (alphaCaMKII), whereas other proteins tested appeared unaffected. Amperometric recordings in chromaffin cells from mice exposed to 68 mg (140 micromol)/kg bw BDE-47 did not reveal changes in catecholamine release parameters. Modest effects on vesicular release and intracellular Ca(2+) in PC12 cells were seen following acute exposure to 20 microM BDE-47. The combined results suggest a post-synaptic mechanism in vivo. CONCLUSION: Early neonatal exposure to a single high dose of BDE-47 causes a reduction of LTP together with changes in postsynaptic proteins involved in synaptic plasticity in the mouse hippocampus.

Absence of Ret signaling in mice causes progressive and late degeneration of the nigrostriatal system.

Support of ageing neurons by endogenous neurotrophic factors such as glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF) may determine whether the neurons resist or succumb to neurodegeneration. GDNF has been tested in clinical trials for the treatment of Parkinson disease (PD), a common neurodegenerative disorder characterized by the loss of midbrain dopaminergic (DA) neurons. BDNF modulates nigrostriatal functions and rescues DA neurons in PD animal models. The physiological roles of GDNF and BDNF signaling in the adult nigrostriatal DA system are unknown. We generated mice with regionally selective ablations of the genes encoding the receptors for GDNF (Ret) and BDNF (TrkB). We find that Ret, but not TrkB, ablation causes progressive and adult-onset loss of DA neurons specifically in the substantia nigra pars compacta, degeneration of DA nerve terminals in striatum, and pronounced glial activation. These findings establish Ret as a critical regulator of long-term maintenance of the nigrostriatal DA system and suggest conditional Ret mutants as useful tools for gaining insights into the molecular mechanisms involved in the development of PD.