The Experts below are selected from a list of 491262 Experts worldwide ranked by ideXlab platform
Hubert R. Dinse - One of the best experts on this subject based on the ideXlab platform.
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Cholinergic gating of improvement of tactile acuity induced by peripheral tactile stimulation
Neuroscience letters, 2008Co-Authors: Barbara Bliem, Martin Tegenthoff, Hubert R. DinseAbstract:As shown in many animal experiments, cholinergic mechanisms participate in N-methyl-d-aspartate (NMDA) receptor-dependent neuroplasticity. Acetylcholine is thought to play a similar role in humans, where it modulates attention and Learning. Here, we tested the cholinergic action on Non-Associative Learning in the tactile domain. We studied the influence of scopolamine, a cholinergic antagonist, on changes in tactile acuity as induced by peripheral tactile coactivation. Coactivation is a Non-Associative tactile Learning protocol and has been shown to improve tactile two-point discrimination of the stimulated finger in addition to selective changes of cortical processing. Under placebo conditions, tactile two-point discrimination was improved on the stimulated index finger. After application of scopolamine, tactile improvement was completely eliminated and tactile acuity was even impaired. No drug effects were found on the left index finger indicating that the drug had no effect on performance per se. The current results provide further evidence that in humans cholinergic mechanisms are also involved in Non-Associative Learning induced by passive stimulation protocols.
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Dopaminergic influences on changes in human tactile acuity induced by tactile coactivation
Experimental Brain Research, 2007Co-Authors: Barbara Bliem, Martin Tegenthoff, Elke Frombach, Patrick Ragert, Frauke Knossalla, Dirk Woitalla, Hubert R. DinseAbstract:As shown in animal experiments, dopaminergic mechanisms participate in N -methyl- d -aspartate (NMDA) receptor-dependent neuroplasticity. Dopamine is thought to play a similar role in humans, where it influences Learning and memory. Here, we tested the dopaminergic action on Learning in the tactile domain. To induce tactile Non-Associative Learning, we applied a tactile coactivation protocol, which is known to improve tactile two-point discrimination of the stimulated finger. We studied the influence of a single oral dose of levodopa (25, 50, 100, 250 or 350 mg) administered preceding the coactivation protocol on changes in tactile performance in different groups of subjects. In addition, 3 × 100 mg levodopa was administered over a time period of 3 h in another group. Under placebo conditions, tactile two-point discrimination was improved on the coactivated index finger. Similar improvement was found when 25, 50 and 250 mg levodopa was applied. On the contrary, tactile improvement was completely eliminated by 1 × 100 and 3 × 100 mg levodopa. No drug effects were found on the left index finger indicating that the drug had no effect on performance per se. In contrast to previous findings in the motor and speech domain, we found that the administration of levodopa exerts either no or even negative effects on Non-Associative Learning in the human somatosensory system. Whenever levodopa is used in neurorehabilitative context, it has to be kept in mind that beneficial effects in the motor or speech domain cannot be easily generalized to other systems.
J.t Metz - One of the best experts on this subject based on the ideXlab platform.
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An artificial neural network stimulating performance of normal subjects and schizophrenics on the Wisconsin card sorting test
Artificial Intelligence in Medicine, 1998Co-Authors: S Berdia, J.t MetzAbstract:Mental diseases such as schizophrenia are being modeled by artificial neural networks in an attempt to understand the underlying neuropathological processes. We studied hospitalized psychiatric patients that met the DSM-IIIR criteria for schizophrenia (N=19), and normal subjects with no psychiatric history (N=18). Performance on the Wisconsin Card Sorting Test (WCST) by schizophrenic patients was poorer than normal subjects as estimated by various scoring measurements. We then modeled an artificial neural network, motivated by biological considerations, that is able to simulate performance of normals and schizophrenics on the WCST. In order to model the complex nature of the WCST, we designed novel Learning rules based on Non-Associative Learning paradigms. We found that there must be a minimum amount of noise, or inherent synaptic instability, for our model to perform similar to schizophrenics.
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An artificial neural network simulating performance of normal subjects and schizophrenics on the Wisconsin Card Sorting Test.
Artificial intelligence in medicine, 1998Co-Authors: S Berdia, J.t MetzAbstract:Mental diseases such as schizophrenia are being modeled by artificial neural networks in an attempt to understand the underlying neuropathological processes. We studied hospitalized psychiatric patients that met the DSM-IIIR criteria for schizophrenia (N=19), and normal subjects with no psychiatric history (N=18). Performance on the Wisconsin Card Sorting Test (WCST) by schizophrenic patients was poorer than normal subjects as estimated by various scoring measurements. We then modeled an artificial neural network, motivated by biological considerations, that is able to simulate performance of normals and schizophrenics on the WCST. In order to model the complex nature of the WCST, we designed novel Learning rules based on Non-Associative Learning paradigms. We found that there must be a minimum amount of noise, or inherent synaptic instability, for our model to perform similar to schizophrenics.
Gang Song - One of the best experts on this subject based on the ideXlab platform.
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habituation desensitization and sensitization of the hering breuer reflex in normal and mecp2 y knockout mice
The Journal of Physiology, 2007Co-Authors: Chi-sang Poon, Gang SongAbstract:In an interesting study published recently in The Journal of Physiology,Stettner et al. (2007) reported that Mecp2−/y knockout (KO) mice devoid of the X-linked methyl-CpG binding protein 2 gene demonstrated prolonged and highly variable postinspiratory vagal efferent activity that correlated with the characteristic breathing arrhythmias in these mutant animals. Furthermore, glutamate microinjections into the pontine Kolliker–Fuse nucleus evoked significantly longer apnoeas with enhanced postinspiratory vagal discharge compared with wild-type (WT) controls. Finally, the authors provided data to suggest that repetitive electrical stimulation of vagal afferents also elicited significantly longer Hering–Breuer reflex (HBR)-like apnoeas in the Mecp2−/y KO mice without any sign of ‘desensitization’ of the reflex. We applaud the authors' elaboration of impaired vagal-pontine control of the respiratory rhythm in Mecp2−/y KO mice. However, we feel obliged to point out that their notion of differing ‘desensitization’ of the vagally induced HBR apnoeas in wild-type and Mecp2−/y KO animals is problematic and is at variance with current understanding of Non-Associative Learning in brain pathways in general and in vagal-pontine mediation of the HBR in particular. Comparison with previous related studies is important because not only does it help to put the significance of the work in perspective, but in this case, it also reveals major discrepancies in interpretation of the results that point to a very different conclusion. For many decades, Non-Associative Learning in the parlance of the behavioural neuroscience literature has been generally thought of as a dual process (habituation or sensitization) corresponding to activity-dependent down- or up-regulation of the response to a continuous or repetitive stimulus (Groves & Thompson, 1970). The notion of desensitization as a novel (and non-trivial) form of Non-Associative Learning was first introduced in this Journal by Siniaia et al. (2000) precisely in the context of fictive HBR modulation of the respiratory frequency (particularly expiratory duration (Poon et al. 2000)) induced by low-intensity, high-frequency vagal electrical stimulation. This notion has led to a general framework of Non-Associative Learning with four base modes (habituation, desensitization, primary sensitization and secondary sensitization), which has proved to harmoniously unify the functional characteristics of Non-Associative Learning reported in many brain systems across animal phyla and sensory modalities (Poon & Young, 2006). Conventionally, habituation is characterized as (among other functional criteria) a down-regulating adaptation with short-term memory (Groves & Thompson, 1970; Poon & Young, 2006). Importantly, the latter remains latent post-stimulation and is activated (recalled) only when stimulated again – a process which has been termed ‘input gating’ (Young et al. 2003; Poon & Young, 2006). Desensitization is distinguished from habituation by the explicit expression of post-stimulation memory rebound and recovery, as desensitization (i.e. secondary habituation) is not subject to input gating. The exponential down-regulation effects of habituation and desensitization have been likened to those of a monophasic or biphasic (without or with memory rebound) neural differentiator or high-pass filter (Poon & Siniaia, 2000; Poon et al. 2000; Poon & Young, 2006). In the vagally induced HBR, desensitization was abolished after lesioning of the Kolliker–Fuse nucleus or systemic administration of the non-competitive NMDA receptor antagonist MK-801 (Poon et al. 2000; Siniaia et al. 2000). A working scheme of vagal-pontine mediation of the HBR and its habituation and desensitization has been proposed previously (Poon & Siniaia, 2000; Siniaia et al. 2000; Poon, 2004; Song & Poon, 2004). The authors of this paper stated that ‘All WT preparations showed a clear desensitization of the HBR in response to repetitive vagal stimulation’. However, from the presented data (Fig. 7A in Stettner et al. 2007) it appears that the shortening of the apnoea duration after repetitive stimulation reflected habituation (in the classical sense) of the HBR instead of desensitization, since a memory rebound was not evident at the cessation of vagal stimulation. Indeed, if anything, the expiratory duration remained longer immediately after both the 1st and 15th stimulation trial compared with resting conditions, showing the memory effects of concomitant secondary (not primary; see Poon & Young, 2006) sensitization of the HBR instead. This post-stimulation sensitization memory appeared to be accentuated in the Mecp2−/y KO animals, as indicated by the sustained apnoeas extending well beyond the vagal stimulation period (Fig. 7B and C). The mechanism of this peculiar secondary sensitization (instead of desensitization) of the HBR in wild-type and Mecp2−/y KO animals is unclear but could potentially result from activation of rapidly adapting pulmonary stretch receptor fibres or even cardiopulmonary C-fibres, as such secondary sensitization effects were not elicited by low-intensity, high-frequency (15–40 μA, 40–80 Hz) vagal electrical stimulation in rats (Poon et al. 2000; Siniaia et al. 2000). The authors also used a repetitive vagal stimulation protocol to induce Non-Associative Learning of the HBR, apparently because the evoked apnoea was not habituated within the 10 s stimulation period due to the strength of the stimulation. Such a repetitive stimulation protocol is routine in studies of Non-Associative Learning in invertebrate sensorimotor pathways to allow for refractory (‘output gating’) of the resultant motor response (Poon & Young, 2006). Since the mammalian respiratory motor response is non-refractory, a continuous (and sufficiently long) vagal stimulus should be as effective as a repetitive one in discerning habituation, sensitization and desensitization (Young et al. 2003), but neither protocol was found to induce secondary sensitization when vagal stimulation was kept at low intensities to obviate artifacts and nerve fatigue in rats (MacDonald et al. 2004). These caveats aside, the authors have provided convincing evidence of deranged vagal-pontine modulation of the respiratory rhythm in Mecp2−/y KO mice, which, when viewed in the proper light, reveals diminished habituation and accentuated secondary sensitization of fictive HBR. The potential roles of pontine postinspiratory activity in mediating the abnormal habituation, desensitization and sensitization of the HBR and resultant breathing arrhythmias remain to be clarified, although neurons with postinspiratory (early expiratory) discharges have been previously identified in the vicinity of the Kolliker–Fuse nucleus in the rat (Song et al. 2006). This Non-Associative Learning perspective should help illuminate the pathogenesis of breathing abnormalities in these mutant animals or those with DNA hypomethylation (Fan et al. 2001), and in patients with Rett syndrome caused by mutations of the MECP2 gene.
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Habituation, desensitization and sensitization of the Hering–Breuer reflex in normal and Mecp2−/y knockout mice
The Journal of Physiology, 2007Co-Authors: Chi-sang Poon, Gang SongAbstract:In an interesting study published recently in The Journal of Physiology,Stettner et al. (2007) reported that Mecp2−/y knockout (KO) mice devoid of the X-linked methyl-CpG binding protein 2 gene demonstrated prolonged and highly variable postinspiratory vagal efferent activity that correlated with the characteristic breathing arrhythmias in these mutant animals. Furthermore, glutamate microinjections into the pontine Kolliker–Fuse nucleus evoked significantly longer apnoeas with enhanced postinspiratory vagal discharge compared with wild-type (WT) controls. Finally, the authors provided data to suggest that repetitive electrical stimulation of vagal afferents also elicited significantly longer Hering–Breuer reflex (HBR)-like apnoeas in the Mecp2−/y KO mice without any sign of ‘desensitization’ of the reflex. We applaud the authors' elaboration of impaired vagal-pontine control of the respiratory rhythm in Mecp2−/y KO mice. However, we feel obliged to point out that their notion of differing ‘desensitization’ of the vagally induced HBR apnoeas in wild-type and Mecp2−/y KO animals is problematic and is at variance with current understanding of Non-Associative Learning in brain pathways in general and in vagal-pontine mediation of the HBR in particular. Comparison with previous related studies is important because not only does it help to put the significance of the work in perspective, but in this case, it also reveals major discrepancies in interpretation of the results that point to a very different conclusion. For many decades, Non-Associative Learning in the parlance of the behavioural neuroscience literature has been generally thought of as a dual process (habituation or sensitization) corresponding to activity-dependent down- or up-regulation of the response to a continuous or repetitive stimulus (Groves & Thompson, 1970). The notion of desensitization as a novel (and non-trivial) form of Non-Associative Learning was first introduced in this Journal by Siniaia et al. (2000) precisely in the context of fictive HBR modulation of the respiratory frequency (particularly expiratory duration (Poon et al. 2000)) induced by low-intensity, high-frequency vagal electrical stimulation. This notion has led to a general framework of Non-Associative Learning with four base modes (habituation, desensitization, primary sensitization and secondary sensitization), which has proved to harmoniously unify the functional characteristics of Non-Associative Learning reported in many brain systems across animal phyla and sensory modalities (Poon & Young, 2006). Conventionally, habituation is characterized as (among other functional criteria) a down-regulating adaptation with short-term memory (Groves & Thompson, 1970; Poon & Young, 2006). Importantly, the latter remains latent post-stimulation and is activated (recalled) only when stimulated again – a process which has been termed ‘input gating’ (Young et al. 2003; Poon & Young, 2006). Desensitization is distinguished from habituation by the explicit expression of post-stimulation memory rebound and recovery, as desensitization (i.e. secondary habituation) is not subject to input gating. The exponential down-regulation effects of habituation and desensitization have been likened to those of a monophasic or biphasic (without or with memory rebound) neural differentiator or high-pass filter (Poon & Siniaia, 2000; Poon et al. 2000; Poon & Young, 2006). In the vagally induced HBR, desensitization was abolished after lesioning of the Kolliker–Fuse nucleus or systemic administration of the non-competitive NMDA receptor antagonist MK-801 (Poon et al. 2000; Siniaia et al. 2000). A working scheme of vagal-pontine mediation of the HBR and its habituation and desensitization has been proposed previously (Poon & Siniaia, 2000; Siniaia et al. 2000; Poon, 2004; Song & Poon, 2004). The authors of this paper stated that ‘All WT preparations showed a clear desensitization of the HBR in response to repetitive vagal stimulation’. However, from the presented data (Fig. 7A in Stettner et al. 2007) it appears that the shortening of the apnoea duration after repetitive stimulation reflected habituation (in the classical sense) of the HBR instead of desensitization, since a memory rebound was not evident at the cessation of vagal stimulation. Indeed, if anything, the expiratory duration remained longer immediately after both the 1st and 15th stimulation trial compared with resting conditions, showing the memory effects of concomitant secondary (not primary; see Poon & Young, 2006) sensitization of the HBR instead. This post-stimulation sensitization memory appeared to be accentuated in the Mecp2−/y KO animals, as indicated by the sustained apnoeas extending well beyond the vagal stimulation period (Fig. 7B and C). The mechanism of this peculiar secondary sensitization (instead of desensitization) of the HBR in wild-type and Mecp2−/y KO animals is unclear but could potentially result from activation of rapidly adapting pulmonary stretch receptor fibres or even cardiopulmonary C-fibres, as such secondary sensitization effects were not elicited by low-intensity, high-frequency (15–40 μA, 40–80 Hz) vagal electrical stimulation in rats (Poon et al. 2000; Siniaia et al. 2000). The authors also used a repetitive vagal stimulation protocol to induce Non-Associative Learning of the HBR, apparently because the evoked apnoea was not habituated within the 10 s stimulation period due to the strength of the stimulation. Such a repetitive stimulation protocol is routine in studies of Non-Associative Learning in invertebrate sensorimotor pathways to allow for refractory (‘output gating’) of the resultant motor response (Poon & Young, 2006). Since the mammalian respiratory motor response is non-refractory, a continuous (and sufficiently long) vagal stimulus should be as effective as a repetitive one in discerning habituation, sensitization and desensitization (Young et al. 2003), but neither protocol was found to induce secondary sensitization when vagal stimulation was kept at low intensities to obviate artifacts and nerve fatigue in rats (MacDonald et al. 2004). These caveats aside, the authors have provided convincing evidence of deranged vagal-pontine modulation of the respiratory rhythm in Mecp2−/y KO mice, which, when viewed in the proper light, reveals diminished habituation and accentuated secondary sensitization of fictive HBR. The potential roles of pontine postinspiratory activity in mediating the abnormal habituation, desensitization and sensitization of the HBR and resultant breathing arrhythmias remain to be clarified, although neurons with postinspiratory (early expiratory) discharges have been previously identified in the vicinity of the Kolliker–Fuse nucleus in the rat (Song et al. 2006). This Non-Associative Learning perspective should help illuminate the pathogenesis of breathing abnormalities in these mutant animals or those with DNA hypomethylation (Fan et al. 2001), and in patients with Rett syndrome caused by mutations of the MECP2 gene.
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phenomenon of non associative Learning in hering breuer reflex simulated by electrical vagal stimulation in rabbits
Acta physiologica Sinica, 2005Co-Authors: Guimin Wang, Gang Song, Heng ZhangAbstract:The purpose of this study was to explore Learning and memory in the Hering-Breuer (HB) reflex simulated by a 60-second-long electrical stimulation of vagus nerve. The responses of phrenic nerve discharge to electrical stimulation (10-100 Hz, 20-60 muA, pulse duration 0.3 ms, for 60 s) of the vagus nerve were observed in rabbits. The results showed that 60-second-long stimulation of vagus nerve produced classic HB reflex, which is composed of two components - lung inflation reflex that is the inhibition of inspiration, and lung deflation reflex that is the facilitation of inspiration. (1) High frequency stimulation (>/=40 Hz, 60 s) of the central end of vagus nerve induced shortening of the inspiratory phase and lengthening of expiratory duration. The inhibitory effect on phrenic discharge was released gradually during sustained vagal stimulation, indicating the habituation of the inhibition. At the cessation of stimulation, the phrenic discharge showed transient post-stimulus rebound. Low frequency stimulation (<40 Hz, 60 s) of the central end of vagus nerve caused an increase in respiratory frequency (f) and shortening of expiratory duration. The excitatory effect on phrenic discharge was also released gradually during the vagal stimulation. The phrenic discharge returned to control level gradually after the removal of the vagal stimulus, indicating short-term potentiation (STP). (2) The habituation of HB reflex was inversely dependent on stimulus intensity and frequency. With an increase in the stimulus frequency or intensity, the degree of the habituation decreased. On the other hand, with the decrease of stimulation intensity and frequency, the degree of the habituation increased. These data indicate a phenomenon of Non-Associative Learning in HB reflex simulated by vagal stimulation. Neural synaptic plasticity and accommodation may exist in the reflex control of respiration in rabbits.
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Phenomenon of Non-Associative Learning in Hering-Breuer reflex simulated by electrical vagal stimulation in rabbits.
Sheng li xue bao : [Acta physiologica Sinica], 2005Co-Authors: Guimin Wang, Gang Song, Heng ZhangAbstract:The purpose of this study was to explore Learning and memory in the Hering-Breuer (HB) reflex simulated by a 60-second-long electrical stimulation of vagus nerve. The responses of phrenic nerve discharge to electrical stimulation (10-100 Hz, 20-60 muA, pulse duration 0.3 ms, for 60 s) of the vagus nerve were observed in rabbits. The results showed that 60-second-long stimulation of vagus nerve produced classic HB reflex, which is composed of two components - lung inflation reflex that is the inhibition of inspiration, and lung deflation reflex that is the facilitation of inspiration. (1) High frequency stimulation (>/=40 Hz, 60 s) of the central end of vagus nerve induced shortening of the inspiratory phase and lengthening of expiratory duration. The inhibitory effect on phrenic discharge was released gradually during sustained vagal stimulation, indicating the habituation of the inhibition. At the cessation of stimulation, the phrenic discharge showed transient post-stimulus rebound. Low frequency stimulation (
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Functional and structural models of pontine modulation of mechanoreceptor and chemoreceptor reflexes.
Respiratory physiology & neurobiology, 2004Co-Authors: Gang Song, Chi-sang PoonAbstract:The dorsolateral and ventrolateral pons (dl-pons, vl-pons) are critical brainstem structures mediating the plasticity of the Hering-Breuer mechanoreflex (HBR) and carotid chemoreflex (CCR). Review of anatomical evidence indicates that dl-pons and vl-pons are connected reciprocally with one another and with medullary nucleus tractus solitarius (NTS) and ventral respiratory group (VRG). With this structural map, functional models of HBR and CCR are proposed in which the respiratory rhythm is modulated by short-term depression (STD) or potentiation (STP) of corresponding primary NTS-VRG and auxiliary pons-VRG excitatory or inhibitory pathways. Behaviorally, STD and STP of respiratory reflexes are akin to Non-Associative Learning such as habituation, sensitization or desensitization to afferent inputs. Computationally, the STD and STP effects amount to signal differentiation and integration in the time domain, or high-pass and low-pass filtering in the frequency domain, respectively. These functional and structural models of pontomedullary signal processing provide a novel conceptual framework that unifies a wealth of experimental observations regarding mechanoreceptor and chemoreceptor reflex control of breathing.
Barbara Bliem - One of the best experts on this subject based on the ideXlab platform.
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Cholinergic gating of improvement of tactile acuity induced by peripheral tactile stimulation
Neuroscience letters, 2008Co-Authors: Barbara Bliem, Martin Tegenthoff, Hubert R. DinseAbstract:As shown in many animal experiments, cholinergic mechanisms participate in N-methyl-d-aspartate (NMDA) receptor-dependent neuroplasticity. Acetylcholine is thought to play a similar role in humans, where it modulates attention and Learning. Here, we tested the cholinergic action on Non-Associative Learning in the tactile domain. We studied the influence of scopolamine, a cholinergic antagonist, on changes in tactile acuity as induced by peripheral tactile coactivation. Coactivation is a Non-Associative tactile Learning protocol and has been shown to improve tactile two-point discrimination of the stimulated finger in addition to selective changes of cortical processing. Under placebo conditions, tactile two-point discrimination was improved on the stimulated index finger. After application of scopolamine, tactile improvement was completely eliminated and tactile acuity was even impaired. No drug effects were found on the left index finger indicating that the drug had no effect on performance per se. The current results provide further evidence that in humans cholinergic mechanisms are also involved in Non-Associative Learning induced by passive stimulation protocols.
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Dopaminergic influences on changes in human tactile acuity induced by tactile coactivation
Experimental Brain Research, 2007Co-Authors: Barbara Bliem, Martin Tegenthoff, Elke Frombach, Patrick Ragert, Frauke Knossalla, Dirk Woitalla, Hubert R. DinseAbstract:As shown in animal experiments, dopaminergic mechanisms participate in N -methyl- d -aspartate (NMDA) receptor-dependent neuroplasticity. Dopamine is thought to play a similar role in humans, where it influences Learning and memory. Here, we tested the dopaminergic action on Learning in the tactile domain. To induce tactile Non-Associative Learning, we applied a tactile coactivation protocol, which is known to improve tactile two-point discrimination of the stimulated finger. We studied the influence of a single oral dose of levodopa (25, 50, 100, 250 or 350 mg) administered preceding the coactivation protocol on changes in tactile performance in different groups of subjects. In addition, 3 × 100 mg levodopa was administered over a time period of 3 h in another group. Under placebo conditions, tactile two-point discrimination was improved on the coactivated index finger. Similar improvement was found when 25, 50 and 250 mg levodopa was applied. On the contrary, tactile improvement was completely eliminated by 1 × 100 and 3 × 100 mg levodopa. No drug effects were found on the left index finger indicating that the drug had no effect on performance per se. In contrast to previous findings in the motor and speech domain, we found that the administration of levodopa exerts either no or even negative effects on Non-Associative Learning in the human somatosensory system. Whenever levodopa is used in neurorehabilitative context, it has to be kept in mind that beneficial effects in the motor or speech domain cannot be easily generalized to other systems.
Catharine H. Rankin - One of the best experts on this subject based on the ideXlab platform.
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Habituation in high-throughput genetic model organisms as a tool to investigate the mechanisms of neurodevelopmental disorders.
Neurobiology of learning and memory, 2020Co-Authors: Lexis D. Kepler, Troy A. Mcdiarmid, Catharine H. RankinAbstract:Abstract Alterations in habituation, a highly conserved form of Non-Associative Learning, are suspected to contribute to a range of the complex behavioural phenotypes present in multiple neurodevelopmental disorders. While progress has been made in understanding the genetics of these disorders through the application of next-generation sequencing and related technologies, the pathogenicity of genetic variants and causes of Learning and memory impairments can be difficult to determine from sequencing data alone. High-throughput genetic model organisms such as the roundworm Caenorhabditis elegans, fruit fly Drosophila melanogaster, and zebrafish Danio rerio offer low-cost and efficient methods to investigate the functions of identified neurodevelopmental disorder risk genes and the functional consequences of specific disorder-associated variants. Here, we review ways assessing habituation has been used in the genotype-first approach to first validate neurodevelopmental disorder candidate genes and now to systematically characterize large candidate gene lists. We then discuss exciting ways habituation, in combination with other techniques, can be used as a tool to assess the pathogenicity of putative genes and genetic variants, uncover and confirm molecular networks, and identify potential therapeutic avenues.
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Insights into the roles of CMK-1 and OGT-1 in interstimulus interval-dependent habituation in Caenorhabditis elegans
Proceedings. Biological sciences, 2018Co-Authors: Evan L. Ardiel, Tiffany A. Timbers, Troy A. Mcdiarmid, Kirsten C. Y. Lee, Javad Safaei, Steven L. Pelech, Catharine H. RankinAbstract:Habituation is a ubiquitous form of Non-Associative Learning observed as a decrement in responding to repeated stimulation that cannot be explained by sensory adaptation or motor fatigue. One of the defining characteristics of habituation is its sensitivity to the rate at which training stimuli are presented-animals habituate faster in response to more rapid stimulation. The molecular mechanisms underlying this interstimulus interval (ISI)-dependent characteristic of habituation remain unknown. In this article, we use behavioural neurogenetic and bioinformatic analyses in the nematode Caenorhabiditis elegans to identify the first molecules that modulate habituation in an ISI-dependent manner. We show that the Caenorhabditis elegans orthologues of Ca2+/calmodulin-dependent kinases CaMK1/4, CMK-1 and O-linked N-acetylglucosamine (O-GlcNAc) transferase, OGT-1, both function in primary sensory neurons to inhibit habituation at short ISIs and promote it at long ISIs. In addition, both cmk-1 and ogt-1 mutants display a rare mechanosensory hyper-responsive phenotype (i.e. larger mechanosensory responses than wild-type). Overall, our work identifies two conserved genes that function in sensory neurons to modulate habituation in an ISI-dependent manner, providing the first insights into the molecular mechanisms underlying the universally observed phenomenon that habituation has different properties when stimuli are delivered at different rates.
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habituation is altered in neuropsychiatric disorders a comprehensive review with recommendations for experimental design and analysis
Neuroscience & Biobehavioral Reviews, 2017Co-Authors: Troy A. Mcdiarmid, Aram C Bernardos, Catharine H. RankinAbstract:Abstract Abnormalities in the simplest form of Learning, habituation, have been reported in a variety of neuropsychiatric disorders as etiologically diverse as Autism Spectrum Disorder, Fragile X syndrome, Schizophrenia, Parkinson’s Disease, Huntington’s Disease, Attention Deficit Hyperactivity Disorder, Tourette’s Syndrome, and Migraine. Here we provide the first comprehensive review of what is known about alterations in this form of Non-Associative Learning in each disorder. Across several disorders, abnormal habituation is predictive of symptom severity, highlighting the clinical significance of habituation and its importance to normal cognitive function. Abnormal habituation is discussed within the greater framework of Learning theory and how it may relate to disease phenotype either as a cause, symptom, or therapy. Important considerations for the design and interpretation of habituation experiments are outlined with the hope that these will aid both clinicians and basic researchers investigating how this simple form of Learning is altered in disease.
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The role of neuropeptides in Learning and memory in Caenorhabditis elegans
Current Opinion in Behavioral Sciences, 2015Co-Authors: Troy A. Mcdiarmid, Evan L. Ardiel, Catharine H. RankinAbstract:C. elegans is an ideal system for behavioral genetic analysis of Learning and memory. Recently a number of papers have highlighted the importance of neuropeptide signaling in this behavioral plasticity. Neuropeptide signaling has been found to modulate the worm's learned preference for smells, tastes, and temperatures associated with feeding state, as well as their response following prolonged exposure to chemo- or mechano-sensory stimuli in Non-Associative Learning paradigms. Depending on the assay, sensory neurons and interneurons have been shown to be both the source of the neuropeptides and the site of action. Most neuropeptide receptors are orphaned and functionally uncharacterized, but are expected to emerge as major modulators of behavior.
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Genetic dissection of memory for associative and Non-Associative Learning in Caenorhabditis elegans.
Genes brain and behavior, 2012Co-Authors: H. L. Lau, Tiffany A. Timbers, R. Mahmoud, Catharine H. RankinAbstract:The distinction between Non-Associative and associative forms of Learning has historically been based on the behavioral training paradigm. Through discovering the molecular mechanisms that mediate Learning, we can develop a deeper understanding of the relationships between different forms of Learning. Here, we genetically dissect short- and long-term memory for a Non-Associative form of Learning, habituation and an associative form of Learning, context conditioning for habituation, in the nematode Caenorhabditis elegans. In short-term chemosensory context conditioning for habituation, worms trained and tested in the presence of either a taste (sodium acetate) or smell (diacetyl) context cue show greater retention of habituation to tap stimuli when compared with animals trained and tested without a salient cue. Long-term memory for olfactory context conditioning was observed 24 h after a training procedure that does not normally induce 24 h memory. Like long-term habituation, this long-term memory was dependent on the transcription factor cyclic AMP-response element-binding protein. Worms with mutations in glr-1 [a non-N-methyl-d-aspartate (NMDA)-type glutamate receptor subunit] showed short-term but not long-term habituation or short- or long-term context conditioning. Worms with mutations in nmr-1 (an NMDA-receptor subunit) showed normal short- and long-term memory for habituation but did not show either short- or long-term context conditioning. Rescue of nmr-1 in the RIM interneurons rescued short- and long-term olfactory context conditioning leading to the hypothesis that these interneurons function to integrate information from chemosensory and mechanosensory systems for associative Learning.