Mechanisms of serotonergic control in fear-related neural circuits and behaviour
<p>Serotonin (5-HT) neurotransmission is strongly implicated in affective psychopathologies, with first-line drugs selectively targeting the 5-HT system. Further evidence for the role of 5-HT as an important regulator of emotional states comes from human gene association studies. These have id...
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| Other Authors: | |
| Format: | Thesis |
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2017
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| _version_ | 1817932658410258432 |
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| author | Sengupta, A |
| author2 | Sharp, T |
| author_facet | Sharp, T Sengupta, A |
| author_sort | Sengupta, A |
| collection | OXFORD |
| description | <p>Serotonin (5-HT) neurotransmission is strongly implicated in affective psychopathologies, with first-line drugs selectively targeting the 5-HT system. Further evidence for the role of 5-HT as an important regulator of emotional states comes from human gene association studies. These have identified polymorphic variants of the 5-HT transporter (5-HTT) gene with reduced transcription efficacy. Lower 5-HTT expression associates with susceptibility to affective disorders and heightened amygdala reactivity to fearful stimuli. The mechanisms by which 5-HTT gene variation leads to altered amygdala function and fear-related behaviour are unknown. The experiments presented in this thesis study these associations in tractable animal models that allow temporal- and circuit-specific control over 5-HT signalling. Specifically, a translationally relevant mouse model of 5-HTT expression variation and an optogenetic approach are used to probe how changes in 5-HT transmission shape fear-related behaviours.</p> <p>Using an array of behavioural tests, it was found that 5-HTT overexpressing (OE) mice exhibit a low-fear/anxiety phenotype that is already established in adolescence, indicating a possible neurodevelopmental trajectory. Acute pharmacological blockade of the 5-HTT at the time of behavioural testing did not rescue the low-fear phenotype in adolescent 5-HTT OE mice, whereas 5-HTT blockade during an early postnatal period did reverse it. These results identify a developmental origin of the fear-related phenotype associated with 5-HTT expression variation.</p> <p>Next, <em>in vivo</em> optogenetic tools were employed during a fear learning task to control neuromodulation of the basal amygdala (BA) by 5-HT neurons arising from the dorsal raphe (DRN). Photoexcitation of the DRN-BA 5-HT projection pathway enhanced fear learning and impaired fear extinction, while photoinhibition caused a fear learning deficit and facilitated fear extinction. Thus, a bidirectional functional role in fear learning for the BA-targeting 5-HT pathway was characterised.</p> <p>The effect of optogenetic photoexcitation of the DRN-BA 5-HT pathway on BA single unit and network activity during the fear learning task was then recorded <em>in vivo</em>. The study revealed that 5-HT projection activation promoted a neurophysiological state (both in terms of individual neuron activity and network oscillations) in the BA that has previously been associated with fear expression.</p> <p>Ex vivo electrophysiology experiments then explored the effect of optogenetic activation of the DRN-BA 5-HT pathway on the BA microcircuitry. These latter experiments identified clear evidence of 5-HT and glutamate co-transmission within the BA, which functioned in a cell type-specific and frequency-dependent manner.</p> <p>Finally, a combination of retrograde tracing and immunohistochemistry was applied to analyse the neurochemical identity of DRN neurons that project to the BA. The majority of these neurons were found to co-express markers for 5-HT and glutamate. To evaluate the contribution of 5-HT transmission from DRN-BA 5-HT projections to fear learning, optogenetics was combined with local infusion of 5-HT receptor antagonists. This experiment demonstrated that photoexcitation-induced enhancement of fear learning was mediated by 5-HT-dependent mechanisms.</p> <p>In summary, this thesis presents new evidence that DRN-BA 5-HT projections exert circuit-, temporal-, and 5-HT receptor-specific regulation of fear-related behaviour. These results highlight the importance of elucidating precise actions of 5-HT transmission in moving towards a more accurate understanding of how the 5-HT system influences emotional states.</p> |
| first_indexed | 2024-03-06T20:37:48Z |
| format | Thesis |
| id | oxford-uuid:333590cf-964d-44dd-8f5b-4d492e15f8b2 |
| institution | University of Oxford |
| last_indexed | 2024-12-09T03:41:25Z |
| publishDate | 2017 |
| record_format | dspace |
| spelling | oxford-uuid:333590cf-964d-44dd-8f5b-4d492e15f8b22024-12-07T12:29:22ZMechanisms of serotonergic control in fear-related neural circuits and behaviourThesishttp://purl.org/coar/resource_type/c_db06uuid:333590cf-964d-44dd-8f5b-4d492e15f8b2ORA Deposit2017Sengupta, ASharp, TBannerman, D<p>Serotonin (5-HT) neurotransmission is strongly implicated in affective psychopathologies, with first-line drugs selectively targeting the 5-HT system. Further evidence for the role of 5-HT as an important regulator of emotional states comes from human gene association studies. These have identified polymorphic variants of the 5-HT transporter (5-HTT) gene with reduced transcription efficacy. Lower 5-HTT expression associates with susceptibility to affective disorders and heightened amygdala reactivity to fearful stimuli. The mechanisms by which 5-HTT gene variation leads to altered amygdala function and fear-related behaviour are unknown. The experiments presented in this thesis study these associations in tractable animal models that allow temporal- and circuit-specific control over 5-HT signalling. Specifically, a translationally relevant mouse model of 5-HTT expression variation and an optogenetic approach are used to probe how changes in 5-HT transmission shape fear-related behaviours.</p> <p>Using an array of behavioural tests, it was found that 5-HTT overexpressing (OE) mice exhibit a low-fear/anxiety phenotype that is already established in adolescence, indicating a possible neurodevelopmental trajectory. Acute pharmacological blockade of the 5-HTT at the time of behavioural testing did not rescue the low-fear phenotype in adolescent 5-HTT OE mice, whereas 5-HTT blockade during an early postnatal period did reverse it. These results identify a developmental origin of the fear-related phenotype associated with 5-HTT expression variation.</p> <p>Next, <em>in vivo</em> optogenetic tools were employed during a fear learning task to control neuromodulation of the basal amygdala (BA) by 5-HT neurons arising from the dorsal raphe (DRN). Photoexcitation of the DRN-BA 5-HT projection pathway enhanced fear learning and impaired fear extinction, while photoinhibition caused a fear learning deficit and facilitated fear extinction. Thus, a bidirectional functional role in fear learning for the BA-targeting 5-HT pathway was characterised.</p> <p>The effect of optogenetic photoexcitation of the DRN-BA 5-HT pathway on BA single unit and network activity during the fear learning task was then recorded <em>in vivo</em>. The study revealed that 5-HT projection activation promoted a neurophysiological state (both in terms of individual neuron activity and network oscillations) in the BA that has previously been associated with fear expression.</p> <p>Ex vivo electrophysiology experiments then explored the effect of optogenetic activation of the DRN-BA 5-HT pathway on the BA microcircuitry. These latter experiments identified clear evidence of 5-HT and glutamate co-transmission within the BA, which functioned in a cell type-specific and frequency-dependent manner.</p> <p>Finally, a combination of retrograde tracing and immunohistochemistry was applied to analyse the neurochemical identity of DRN neurons that project to the BA. The majority of these neurons were found to co-express markers for 5-HT and glutamate. To evaluate the contribution of 5-HT transmission from DRN-BA 5-HT projections to fear learning, optogenetics was combined with local infusion of 5-HT receptor antagonists. This experiment demonstrated that photoexcitation-induced enhancement of fear learning was mediated by 5-HT-dependent mechanisms.</p> <p>In summary, this thesis presents new evidence that DRN-BA 5-HT projections exert circuit-, temporal-, and 5-HT receptor-specific regulation of fear-related behaviour. These results highlight the importance of elucidating precise actions of 5-HT transmission in moving towards a more accurate understanding of how the 5-HT system influences emotional states.</p> |
| spellingShingle | Sengupta, A Mechanisms of serotonergic control in fear-related neural circuits and behaviour |
| title | Mechanisms of serotonergic control in fear-related neural circuits and behaviour |
| title_full | Mechanisms of serotonergic control in fear-related neural circuits and behaviour |
| title_fullStr | Mechanisms of serotonergic control in fear-related neural circuits and behaviour |
| title_full_unstemmed | Mechanisms of serotonergic control in fear-related neural circuits and behaviour |
| title_short | Mechanisms of serotonergic control in fear-related neural circuits and behaviour |
| title_sort | mechanisms of serotonergic control in fear related neural circuits and behaviour |
| work_keys_str_mv | AT senguptaa mechanismsofserotonergiccontrolinfearrelatedneuralcircuitsandbehaviour |