Papers by Inge G Wolterink-Donselaar
bioRxiv (Cold Spring Harbor Laboratory), Mar 14, 2024
bioRxiv (Cold Spring Harbor Laboratory), Oct 16, 2023
Adaptive responses to challenging environments depend on optimal function of the locus coeruleus ... more Adaptive responses to challenging environments depend on optimal function of the locus coeruleus (LC), the brain's main source of noradrenaline and primary mediator of the initial stress response. Built-in systems that exert regulatory control over the LC are largely unidentified. A good candidate system is neuropeptide Y (NPY), which is traditionally linked to anxiety-relief. Currently, the endogenous source of NPY to the LC, and how NPY-expressing neurons modulate the noradrenergic system to regulate anxiety remain unclear. We here identify, in mice, a novel NPYexpressing neuronal population (peri-LCNPY) neighboring LC noradrenergic neurons that locally innervates the pericoerulean space. Moreover, we demonstrate that stress engages peri-LCNPY neurons, increasing their excitability. Mimicking peri-LCNPY neuronal activation using ex vivo chemogenetics suppresses LC noradrenergic neuron activity, via an NPY Y1 receptor-mediated mechanism. Furthermore, in vivo chemogenetic stimulation of peri-LCNPY neurons results in Y1Rdependent anxiety-relief. Conversely, inhibiting peri-LCNPY neurons increases anxiety-like behaviors. Together, we establish a causal role for peri-LCNPY-mediated neuromodulation of the LC in the regulation of anxiety, providing novel insights in the endogenous mechanisms underlying adaptive responses to adversity.
PubMed, Nov 1, 1989
In order to create optimal conditions for the acquisition of i.v. cocaine self-administration in ... more In order to create optimal conditions for the acquisition of i.v. cocaine self-administration in the rat, three groups of rats were deprived of food to different extents in order to obtain body weight reductions of 5 to 15, 15 to 25 and 25 to 35% of the pre-experimental body weights, and were tested for five consecutive 6-hr sessions in a continuous reinforcement procedure for self-administration of cocaine (0.12 mg/ml) or saline. Self-administration interacted with weight loss and indicated that: 1) a minimum level of 15 to 25% weight loss was required to obtain cocaine self-administration; 2) weight loss-induced potentiation of cocaine self-administration resulted from an interaction of increased nonspecific lever pressing activity and increased reinforcing effects of the compound; and 3) optimal differentiation between cocaine- and saline-induced responding was obtained at 15 to 25% weight loss. Daily pretreatment during the five test sessions, with 0.1 to 1.0 mg/kg of naltrexone or 43 to 375 micrograms/kg of haloperidol, dose-dependently decreased the number of cocaine (0.12 mg/ml) self-injections. Naltrexone pretreatment, and to a lesser extent haloperidol pretreatment, appeared to affect cocaine self-administration in a specific manner; both treatments affected responding on the reinforced lever, but not responding on the nonreinforced lever. Self-administration of 0.06 mg/ml of cocaine tended to be decreased by naltrexone (1 mg/kg) and haloperidol (375 micrograms/kg); whereas self-administration induced by 0.25 mg/ml of cocaine was not significantly affected by naltrexone or haloperidol. Both treatments failed to affect self-administration of saline.(ABSTRACT TRUNCATED AT 250 WORDS)
European Neuropsychopharmacology, 2010
Nature Communications
Stress can cause overconsumption of palatable high caloric food. Despite the important role of st... more Stress can cause overconsumption of palatable high caloric food. Despite the important role of stress eating in obesity and (binge) eating disorders, its underlying neural mechanisms remain unclear. Here we demonstrate in mice that stress alters lateral hypothalamic area (LHA) control over the ventral tegmental area (VTA), thereby promoting overconsumption of palatable food. Specifically, we show that glutamatergic LHA neurons projecting to the VTA are activated by social stress, after which their synapses onto dopamine neurons are potentiated via AMPA receptor subunit alterations. We find that stress-driven strengthening of these specific synapses increases LHA control over dopamine output in key target areas like the prefrontal cortex. Finally, we demonstrate that while inducing LHA-VTA glutamatergic potentiation increases palatable fat intake, reducing stress-driven potentiation of this connection prevents such stress eating. Overall, this study provides insights in the neural ci...
<p>Bar blackness indicates the peak effect of the process. P10: postnatal day 10, 1H: 1 hou... more <p>Bar blackness indicates the peak effect of the process. P10: postnatal day 10, 1H: 1 hour post-eFS, 3D: 3 days post-eFS, 14D: 14 days post-eFS, 56D: 56 days post-eFS, Glu/Gln cycle: glutamate/glutamine cycle.</p
Frontiers in Behavioral Neuroscience
Social stress is a major contributor to neuropsychiatric issues such as depression, substance abu... more Social stress is a major contributor to neuropsychiatric issues such as depression, substance abuse and eating disorders. The ventral tegmental area (VTA) is involved in the effects of stress on cognitive and emotional processes perturbed in these disorders. However, the VTA is a cellularly heterogeneous brain area and it remains unclear which of its neuronal populations make up the social stress-sensitive ensemble. The current study characterizes the molecular, topographical and functional properties of VTA social stress-activated cells. First, we used immunohistochemical analysis of Fos protein, a marker of recent increased neuronal activity, to show that acute social stress activates a mainly neuronal ensemble in the VTA (VTASocial stress neurons). Topographical analysis showed that this ensemble, which comprises ∼11% of all VTA neurons, occurs across VTA subregions. Further analysis showed that approximately half of the VTASocial stress neurons express the dopamine synthesis rat...
<p>Gene expression levels as determined by qPCR (Rn) in normothermic (NT) and hyperthermic ... more <p>Gene expression levels as determined by qPCR (Rn) in normothermic (NT) and hyperthermic (HT) animals compared to fold-change in expression of 5 genes as detected by microarray analysis (Rm). <i>P</i> < 0.05 was considered significant (one-tailed Student’s t-test). Indicated are mean ± standard error of the mean.</p
<p>(A, C, E, G) Representative images of <i>Nrxn1</i>, <i>Dpysl3</i>... more <p>(A, C, E, G) Representative images of <i>Nrxn1</i>, <i>Dpysl3</i>, <i>Ptprd</i>, and <i>Slit2</i> gene expression in the hippocampus of NT (left panel) and HT (right panel) animals three days after eFS. (B, D, F, H) Comparison of <i>Nrxn1</i>, <i>Dpysl3</i>, <i>Ptprd</i>, and <i>Slit2</i> gene expression levels in subfields of the hippocampus in HT (<i>n</i> = 9, red bars) animals compared to NT (<i>n</i> = 9, blue bars) littermates. <i>Ptprd</i> is upregulated in the CA2 subfield of the hippocampus of HT animals, * indicates a significant difference of <i>P</i> = 0.0097, littermate-paired Student’s t-test. Bars represents mean ± standard error of the mean. Scalebars in panel A, C, E, and G: 500μm.</p
<p>Hierarchical clustering analysis of differentially expressed genes (930) in all experime... more <p>Hierarchical clustering analysis of differentially expressed genes (930) in all experimental littermate couples (1 hour, 3 and 14 days post-eFS). Rows depict differential expression levels per HT/NT littermate couple, per time-point after eFS. Clustering was performed based on gene and sample clustering using Pearson correlation on average linkage. Tree cluster, right from heat-map, shows hierarchical distance between samples from the different time points. Differential gene expression (log2(Fc) between HT/NT littermate couples is shown in the heatmap as upregulated (red), downregulated (green), or no change (white) according to colored-scale bar.</p
International journal of obesity (2005), Jan 21, 2017
Dopamine (DA) signalling in the brain is necessary for feeding behaviour, and alterations in the ... more Dopamine (DA) signalling in the brain is necessary for feeding behaviour, and alterations in the DA system have been linked to obesity. However, the precise role of DA in the control of food intake remains debated. On the one hand, food reward and motivation are associated with enhanced DA activity. On the other hand, psychostimulant drugs that increase DA signalling suppress food intake. This poses the questions of how endogenous DA neuronal activity regulates feeding, and whether enhancing DA neuronal activity would either promote or reduce food intake. Here, we used designer receptors exclusively activated by designer drugs (DREADD) technology to determine the effects of enhancing DA neuronal activity on feeding behaviour. We chemogenetically activated selective midbrain DA neuronal subpopulations and assessed the effects on feeding microstructure in rats. Treatment with the psychostimulant drug amphetamine or the selective DA reuptake inhibitor GBR 12909 significantly suppressed...
<p>(A) Neurofilament (NF) immunostaining in the hippocampus of a normothermic (NT) control ... more <p>(A) Neurofilament (NF) immunostaining in the hippocampus of a normothermic (NT) control animal, 14 days post-hyperthermia exposure. Square marks subfield enlargement; panel B. (B) Immunostaining for NF in the stratum lucidum of NT control animal (left panel) and in hyperthermia-exposed (HT) littermate (right panel). (C) Comparison of NF-based DAB staining in the stratum lucidum between NT and HT littermates. All HT (<i>n</i> = 10) animals showed increased DAB-staining in the stratum lucidum. Pair-wise comparison of DAB-staining intensities showed increased NF expression in HT animals compared to NT littermates (<i>n</i> = 10), Wilcoxon signed-rank test, * indicates a significance of <i>P</i> = 0.0049. Tukey-style box plots. Scalebars: 100 μm.</p
PLOS ONE, 2015
Febrile seizures are the most prevalent type of seizures among children up to 5 years of age (2-4... more Febrile seizures are the most prevalent type of seizures among children up to 5 years of age (2-4% of Western-European children). Complex febrile seizures are associated with an increased risk to develop temporal lobe epilepsy. To investigate short-and long-term effects of experimental febrile seizures (eFS), we induced eFS in highly febrile convulsionsusceptible C57BL/6J mice at post-natal day 10 by exposure to hyperthermia (HT) and compared them to normotherm-exposed (NT) mice. We detected structural reorganization in the hippocampus 14 days after eFS. To identify molecular candidates, which entrain this structural reorganization , we investigated temporal changes in mRNA expression profiles eFS 1 hour to 56 days after eFS. We identified 931 regulated genes and profiled several candidates using in situ hybridization and histology at 3 and 14 days after eFS. This is the first study to report genome-wide transcriptome analysis after eFS in mice. We identify temporal regulation of multiple processes, such as stress-, immune-and inflammatory responses, glia activation, glutamate-glutamine cycle and myelination. Identification of the short-and long-term changes after eFS is important to elucidate the mechanisms contributing to epileptogenesis.
European Neuropsychopharmacology, 2015
European Neuropsychopharmacology, 2019
Life Sciences, 1988
The *effect of the vasopressin neuropeptide desglycinamide', (Arg 1 vasopressin (DGAVP) on the ac... more The *effect of the vasopressin neuropeptide desglycinamide', (Arg 1 vasopressin (DGAVP) on the acquisition of intravenous cocaine self-administration was studied. Rats were tested under conditions of reduced body weight in a continuous reinforcement operant procedure, during five daily 3 h sessions. Under these conditions, the rate of self:pdministration obtained with 0.125 and 0.25, but not 0.063 mg.ml cocaine, exceeded the rate obtained with saline. Daily pretreatment with DGAVP (5 pg{rat, s.c.) decreased self-administration of 0.125 and 0.25 mg.ml cocaine to the level obtained with saipe, but had no effect on selfadministration of 0.063 mg .ml cocaine and saline. Using a similar procedure, it was shown that daily intracerebroventricuiar pretreatment with vasopressin antiqerum significantly increased self-administration of 0.125 mg.ml '* Present address:
European Journal of Pharmacology, 1989
Experimentally naive rats were implanted with a cannula in the lateral ventricle of the brain and... more Experimentally naive rats were implanted with a cannula in the lateral ventricle of the brain and were allowed to self-administer heroin in doses of 0.125, 0.25, 0.5, 1 or 2 micrograms/infusion or placebo for five daily sessions of 3 h. The number of self-injections was related to the unit dose in an inverted U-shaped manner: the 0.5 microgram/infusion dose induced the highest infusion rate. The total heroin intake was proportionally related to the unit dose. A hot-plate test performed immediately after the fourth session revealed no analgesic effects in any of the groups that self-administered heroin. A naloxone (10 mg/kg) challenge given immediately after the fifth session induced very mild withdrawal signs only in the group that administered the highest dose of heroin. The results indicate that rats readily acquire intraventricular heroin self-administration behaviour and suggest that the rewarding effects of heroin can be dissociated from its analgesic and physical dependence-inducing effects.
Physiological Reports
The DMH is known to regulate brown adipose tissue (BAT) thermogenesis via projections to sympathe... more The DMH is known to regulate brown adipose tissue (BAT) thermogenesis via projections to sympathetic premotor neurons in the raphe pallidus, but there is evidence that the periaqueductal gray (PAG) is also an important relay in the descending pathways regulating thermogenesis. The anatomical projections from the DMH to the PAG subdivisions and their function are largely elusive, and may differ per anterior-posterior level from bregma. We here aimed to investigate the anatomical projections from the DMH to the PAG along the entire anterior-posterior axis of the PAG, and to study the role of these projections in thermogenesis in Wistar rats. Anterograde channel rhodopsin viral tracing showed that the DMH projects especially to the dorsal and lateral PAG. Retrograde rabies viral tracing confirmed this, but also indicated that the PAG receives a diffuse input from the DMH and adjacent hypothalamic subregions. We aimed to study the role of the identified DMH to PAG projections in thermogenesis in conscious rats by specifically activating them using a combination of canine adenovirus-2 (CAV2Cre) and Credependent designer receptor exclusively activated by designer drugs (DREADD) technology. Chemogenetic activation of DMH to PAG projections increased BAT temperature and core body temperature, but we cannot exclude the possibility that at least some thermogenic effects were mediated by adjacent hypothalamic subregions due to difficulties in specifically targeting the DMH and distinct subdivisions of the PAG because of diffuse virus expression. To conclude, our study shows the complexity of the anatomical and functional connection between the hypothalamus and the PAG, and some technical challenges in studying their connection.
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Papers by Inge G Wolterink-Donselaar