Browsing by Subject "PREPULSE INHIBITION"

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  • Morello, Francesca; Voikar, Vootele; Parkkinen, Pihla; Panhelainen, Anne; Rosenholm, Marko; Makkonen, Aki; Rantamäki, Tomi; Piepponen, Petteri; Aitta-aho, Teemu; Partanen, Juha (2020)
    The neural circuits regulating motivation and movement include midbrain dopaminergic neurons and associated inhibitory GABAergic and excitatory glutamatergic neurons in the anterior brainstem. Differentiation of specific subtypes of GABAergic and glutamatergic neurons in the mouse embryonic brainstem is controlled by a transcription factorTal1. This study characterizes the behavioral and neurochemical changes caused by the absence ofTal1function. TheTal1(cko)mutant mice are hyperactive, impulsive, hypersensitive to reward, have learning deficits and a habituation defect in a novel environment. Only minor changes in their dopaminergic system were detected. Amphetamine induced striatal dopamine release and amphetamine induced place preference were normal inTal1(cko)mice. Increased dopamine signaling failed to stimulate the locomotor activity of theTal1(cko)mice, but instead alleviated their hyperactivity. Altogether, theTal1(cko)mice recapitulate many features of the attention and hyperactivity disorders, suggesting a role forTal1regulated developmental pathways and neural structures in the control of motivation and movement.
  • Rikandi, Eva; Mäntylä, Teemu; Lindgren, Maija; Kieseppä, Tuula; Suvisaari, Jaana; Raij, Tuukka T. (2022)
    Background: Psychotic disorders have been suggested to derive from dysfunctional integration of signaling between brain regions. Earlier studies have found several changes in functional network synchronization as well as altered network topology in patients with psychotic disorders. However, studies have used mainly resting-state that makes it more difficult to link functional alterations to any specific stimulus or experience. We set out to examine functional connectivity as well as graph (topological) measures and their association to symptoms in first-episode psychosis patients during movie viewing. Our goal was to understand whole-brain functional dynamics of complex naturalistic information processing in psychosis and changes in brain functional organization related to symptoms. Methods: 71 first-episode psychosis patients and 57 control subjects watched scenes from the movie Alice in Wonderland during 3 T fMRI. We compared functional connectivity and graph measures indicating integration, segregation and centrality between groups, and examined the association between topology and symptom scores in the patient group. Results: We identified a subnetwork with predominantly decreased links of functional connectivity in firstepisode psychosis patients. The subnetwork was mainly comprised of nodes of and links between the cinguloopercular, sensorimotor and default-mode networks. In topological measures, we observed between-group differences in properties of centrality. Conclusions: Functional brain networks are affected during naturalistic information processing already in the early stages of psychosis, concentrated in salience- and cognitive control-related hubs and subnetworks. Understanding these aberrant dynamics could add to better targeted cognitive and behavioral interventions in the early stages of psychotic disorders.
  • Garcia-Gonzalez, Judit; Brock, Alistair J.; Parker, Matthew O.; Riley, Riva J.; Joliffe, David; Sudwarts, Ari; Teh, Muy-Teck; Busch-Nentwich, Elisabeth M.; Stemple, Derek L.; Martineau, Adrian R.; Kaprio, Jaakko; Palviainen, Teemu; Kuan, Valerie; Walton, Robert T.; Brennan, Caroline H. (2020)
    To facilitate smoking genetics research we determined whether a screen of mutagenized zebrafish for nicotine preference could predict loci affecting smoking behaviour. From 30 screened F-3 sibling groups, where each was derived from an individual ethyl-nitrosurea mutagenized F-0 fish, two showed increased or decreased nicotine preference. Out of 25 inactivating mutations carried by the F-3 fish, one in the slit3 gene segregated with increased nicotine preference in heterozygous individuals. Focussed SNP analysis of the human SLIT3 locus in cohorts from UK (n=863) and Finland (n=1715) identified two variants associated with cigarette consumption and likelihood of cessation. Characterisation of slit3 mutant larvae and adult fish revealed decreased sensitivity to the dopaminergic and serotonergic antagonist amisulpride, known to affect startle reflex that is correlated with addiction in humans, and increased htr1aa mRNA expression in mutant larvae. No effect on neuronal pathfinding was detected. These findings reveal a role for SLIT3 in development of pathways affecting responses to nicotine in zebrafish and smoking in humans.
  • Lisboa, S. F.; Issy, A. C.; Biojone, C.; Montezuma, K.; Fattori, V.; Del-Bel, E. A.; Guimaraes, F. S.; Cunha, F. Q.; Verri, W. A.; Joca, S. R. L. (2018)
    Preclinical and clinical evidence suggests pro-inflammatory cytokines might play an important role in the neurobiology of schizophrenia and stress-related psychiatric disorders. Interleukin-18 (IL-18) is a member of the IL-1 family of cytokines and it is widely expressed in brain regions involved in emotional regulation. Since IL-18 involvement in the neurobiology of mental illnesses, including schizophrenia, remains unknown, this work aimed at investigating the behavior of IL-18 null mice (KO) in different preclinical models: 1. the prepulse inhibition test (PPI), which provides an operational measure of sensorimotor gating and schizophrenic-like phenotypes; 2. amphetamine-induced hyperlocomotion, a model predictive of antipsychotic activity; 3. resident intruder test, a model predictive of aggressive behavior. Furthermore, the animals were submitted to models used to assess depressive- and anxiety-like behavior. IL-18KO mice showed impaired baseline PPI response, which was attenuated by D-amphetamine at a dose that did not modify PPI response in wild-type (WT) mice, suggesting a hypodopaminergic prefrontal cortex function in those mice. D-Amphetamine, however, induced hyperlocomotion in IL-18KO mice compared to their WT counterparts, suggesting hyperdopaminergic activity in the midbrain. Moreover, IL-18KO mice presented increased basal levels of IL-1 beta levels in the hippocampus and TNF-alpha in the prefrontal cortex, suggesting an overcompensation of IL-18 absence by increased levels of other proinflammatory cytokines. Although no alteration was observed in the forced swimming or in the elevated plus maze tests in naive IL-18KO mice, these mice presented anxiogenic-like behavior after exposure to repeated forced swimming stress. In conclusion, deletion of the IL-18 gene resembled features similar to symptoms observed in schizophrenia (positive and cognitive symptoms, aggressive behavior), in addition to increased susceptibility to stress. The IL-18KO model, therefore, could provide new insights into how changes in brain immunological homeostasis induce behavioral changes related to psychiatric disorders, such as schizophrenia.
  • Rosenholm, Marko; Paro, Emmi; Antila, Hanna; Voikar, Vootele; Rantamäki, Tomi (2017)
    Brain development is a complex process regulated by genetic programs and activity-dependent neuronal connectivity. Anesthetics profoundly alter neuronal excitability, and anesthesia during early brain development has been consistently associated with neuroapoptosis, altered synaptogenesis, and persistent behavioral abnormalities in experimental animals. However, the depth, and even more the duration and developmental time point(s) of exposure to anesthesia determine the neuropathological and long-term behavioral consequences of anesthetics. Here, we have investigated adulthood phenotypic changes induced by repeated but brief (30 min) isoflurane anesthesia delivered during two distinct developmental periods in male mice. A set of animals were subjected to anesthesia treatments at postnatal days 7, 8 and 9 (P7-9) when the animals are susceptible to anesthesia-induced neuroapoptosis and reduced synaptogenesis. To control the potential influence of (handling) stress, a separate group of animals underwent repeated maternal separations of similar durations. Another set of animals were exposed to the same treatments at postnatal days 15, 16 and 17 (P15-17), a developmental time period when anesthetics have been shown to increase synaptogenesis. Starting from postnatal week 9 the mouse phenotype was evaluated using a battery of behavioral tests that assess general locomotor activity (home cage activity, open field), learning and memory (water maze) and depression- (saccharin preference, forced swim test), anxiety- (light-dark box, stress-induced hyperthermia) and schizophrenia- (nesting, prepulse inhibition) related endophenotypes. Apart from mild impairment in spatial navigation memory, exposure to anesthesia treatments during P7-9 did not bring obvious behavioral alterations in adult animals. Importantly, maternal separation during the same developmental period produced a very similar phenotype during the water maze. Mice exposed to anesthesia during P15-17 showed mild hyperactivity and risk-taking behavior in adulthood, but were otherwise normal. We conclude that significantly longer administration periods are needed in order for early-life repeated exposures to anesthetics to produce behavioral alterations in adult mice.
  • Mätlik, Kärt; Võikar, Vootele; Vilenius, Carolina; Kulesskaya, Natalia; Andressoo, Jaan-Olle (2018)
    Glial cell line-derived neurotrophic factor (GDNF) promotes the survival of dopaminergic neurons in vitro and in vivo. For this reason, GDNF is currently in clinical trials for the treatment of Parkinson’s disease (PD). However, how endogenous GDNF influences dopamine system function and animal behavior is not fully understood. We recently generated GDNF hypermorphic mice that express increased levels of endogenous GDNF from the native locus, resulting in augmented function of the nigrostriatal dopamine system. Specifically, Gdnf wt/hyper mice have a mild increase in striatal and midbrain dopamine levels, increased dopamine transporter activity, and 15% increased numbers of midbrain dopamine neurons and striatal dopaminergic varicosities. Since changes in the dopamine system are implicated in several neuropsychiatric diseases, including schizophrenia, attention deficit hyperactivity disorder (ADHD) and depression, and ectopic GDNF delivery associates with side-effects in PD models and clinical trials, we further investigated Gdnf wt/hyper mice using 20 behavioral tests. Despite increased dopamine levels, dopamine release and dopamine transporter activity, there were no differences in psychiatric disease related phenotypes. However, compared to controls, male Gdnf wt/hyper mice performed better in tests measuring motor function. Therefore, a modest elevation of endogenous GDNF levels improves motor function but does not induce adverse behavioral outcomes.