Background: Anxiety disorders affect close to 10% of the world’s population, accounting for 30% o... more Background: Anxiety disorders affect close to 10% of the world’s population, accounting for 30% of the global non-fatal disease burden. Although their aetiology remains unknown, it has been suggested that anxiety disorders might occur in response to alterations in the gut-brain axis (GBA), the bi-directional communication system between the gut and the brain. The current study aimed to determine whether the well-characterized animal model of neuropsychopathology, the “two-hit model” (maternal infection combined with adolescent cannabinoid exposure), produced abnormalities in the GBA in association with anxiety-like behaviours.
Method: Pregnant Wistar rats were administered the viral mimetic PolyI:C on gestational day 19 and offspring were administered the synthetic cannabinoid HU210 from postnatal days 35–48. Evidence of GBA activation was assessed in the hypothalamus and fecal samples from offspring. Given anxiety disorders affect twice as many females as males, gender differences were also investigated.
Results: Male offspring exhibited no significant outcomes. Female offspring exhibited an increased hypothalamic inflammatory profile, increased hypothalamic CRHR1 mRNA, and decreased fecal expression of the anxiety-reducing bacteria Bifidobacterium longum, however, no anxiety-like behaviour was detected.
Conclusion: These results indicate that the rat two-hit model, well documented to produce behavioural and neuroanatomical abnormalities, also produces GBA disruptions. The results also demonstrate significant sex differences, suggesting that this model may be useful for investigating the role of the GBA in the aetiology of neurodevelopmental disorders.
Background:
Drug addictions is a complex neuropsychiatric disorder that causes significant socie... more Background: Drug addictions is a complex neuropsychiatric disorder that causes significant societal and personal harm. Current research suggests that drugs of abuse such as cocaine disrupt stress response pathways including the hypothalamic-pituitary-adrenal (HPA) axis. Altered HPA function is linked with abnormal responses to stress and is considered a key substrate withdrawal and relapse. The corticotrophin-releasing-hormone (CRH) cells of the paraventricular nucleus (PVN) strongly modulate the HPA axis, although it is currently unknown how they are influenced by cocaine. We applied electrophysiological and in vivo Ca2+ recording approaches to detect cocaine-induced changes in these PVN neurons. Methods: Male and female CRH-IRES-Cre::td-tomato mice received injections of cocaine (15mg/kg i.p.) or vehicle (saline) for 7-10 days. For electrophysiology experiments, one day later patch clamp recordings were made from TD-positive cells in the PVN (n=20 mice; n=85 cells). For photometry experiments, mice were injected with GCaMP6f in the PVN, followed by a fibre optic cannula. Seven days post cocaine administration stress- like behaviour was induced and assessed over two counterbalanced conditions: a robotic remote controlled bug or a looming shadow. Next, c-Fos immunohistochemistry was performed to assess stress reactivity in the PVN. Results: Compared to controls, an increase in mEPSC frequency and latency to first spike were observed in cocaine exposed animals. Cocaine also tended to increase the number of cells showing burst versus regular firing. Saline and cocaine exposed mice showed Ca2+ transients in response to the introduction of a robobug or a looming shadow. Cocaine exposed mice displayed pronounced stress-like behaviour in response to the looming shadow, such as hiding. Discussion: These results indicate that cocaine enhances excitatory drive to PVN CRH neurons. Moreover, an increased latency to first spike may result from adaptations in CRH neurons to limit drug-induced increases in CRH cell activity. Further work is currently underway to determine if these changes are linked with enhanced cellular and behavioural reactivity to stress.
Preferred Format: POSTER Background: Accumulating evidence suggests the psychopathology of anxiet... more Preferred Format: POSTER Background: Accumulating evidence suggests the psychopathology of anxiety involves the bi-directional relationship between the gastrointestinal (GI) tract and the brain, with GI abnormalities a significant co-morbidity of anxiety disorders. Maternal infection and adolescent cannabis exposure are two environmental risk factors that can lead to the development of an anxiety disorder. Using a rat model, we hypothesised that a combination of the two risk factors (two-hit) would produce GI inflammation and integrity disruptions in association with anxiety-like behaviour. Methods: Pregnant Wistar rats were exposed to polyI:C or saline on gestational day 19. On postnatal day (PND) 35 offspring received daily injections of the synthetic cannabinoid HU210 or control for 14 days. Gut and brain tissue was collected on PND 50 (adolescence) and PND 90 (adulthood). Molecular analyses were performed to assess GI inflammation and integrity. Adult offspring (PND 100) were tested for anxiety-like behavior using elevated plus maze and Ethovision XT TM software. Results: Initial results indicate that in comparison to controls, two-hit PND 50 male and female offspring have a decreased inflammatory response in the colon and PND 50 male offspring display evidence of altered GI integrity. No inflammatory or GI abnormalities were detected in PND 90 offspring. Both male and female adult offspring exhibited no evidence of anxiety-like behaviour, however, male offspring showed a significant latency to enter the open arms of the elevated plus maze, indicative of avoidance or perhaps altered goal-directed and motivated behaviour. Conclusion: The preliminary results suggest that combination of the two risk factors decreases intestinal inflammation and induces subtle alterations in GI integrity, but does not produce overt anxiety-like behaviour. Interestingly, there were sex and age differences in these responses. Given these results, this research indicates that this animal model may not be useful to study the underlying mechanisms of anxiety disorders.
Background: Anxiety disorders affect close to 10% of the world’s population, accounting for 30% o... more Background: Anxiety disorders affect close to 10% of the world’s population, accounting for 30% of the global non-fatal disease burden. Although their aetiology remains unknown, it has been suggested that anxiety disorders might occur in response to alterations in the gut-brain axis (GBA), the bi-directional communication system between the gut and the brain. The current study aimed to determine whether the well-characterized animal model of neuropsychopathology, the “two-hit model” (maternal infection combined with adolescent cannabinoid exposure), produced abnormalities in the GBA in association with anxiety-like behaviours. Method: Pregnant Wistar rats were administered the viral mimetic PolyI:C on gestational day 19 and offspring were administered the synthetic cannabinoid HU210 from postnatal days 35–48. Evidence of GBA activation was assessed in the hypothalamus and fecal samples from offspring. Given anxiety disorders affect twice as many females as males, gender differences were also investigated. Results: Male offspring exhibited no significant outcomes. Female offspring exhibited an increased hypothalamic inflammatory profile, increased hypothalamic CRHR1 mRNA, and decreased fecal expression of the anxiety-reducing bacteria Bifidobacterium longum, however, no anxiety-like behaviour was detected. Conclusion: These results indicate that the rat two-hit model, well documented to produce behavioural and neuroanatomical abnormalities, also produces GBA disruptions. The results also demonstrate significant sex differences, suggesting that this model may be useful for investigating the role of the GBA in the aetiology of neurodevelopmental disorders.
Background: Anxiety disorders affect close to 10% of the world’s population, accounting for 30% o... more Background: Anxiety disorders affect close to 10% of the world’s population, accounting for 30% of the global non-fatal disease burden. Although their aetiology remains unknown, it has been suggested that anxiety disorders might occur in response to alterations in the gut-brain axis (GBA), the bi-directional communication system between the gut and the brain. The current study aimed to determine whether the well-characterized animal model of neuropsychopathology, the “two-hit model” (maternal infection combined with adolescent cannabinoid exposure), produced abnormalities in the GBA in association with anxiety-like behaviours. Method: Pregnant Wistar rats were administered the viral mimetic PolyI:C on gestational day 19 and offspring were administered the synthetic cannabinoid HU210 from postnatal days 35–48. Evidence of GBA activation was assessed in the hypothalamus and fecal samples from offspring. Given anxiety disorders affect twice as many females as males, gender differences ...
Background: Although the aetiology of schizophrenia remains unknown, it has been suggested that i... more Background: Although the aetiology of schizophrenia remains unknown, it has been suggested that it might occur in response to alterations in the gut-brain axis (GBA), the bi-directional communication system between the gut and the brain. The current study aimed to determine whether the "two-hit" animal model of neuro-psychopathology (maternal immune activation combined with adolescent cannabinoid exposure), produced abnormalities in the GBA Method: Pregnant Wistar rats were administered the viral mimetic polyI:C on gestational day 19 and offspring were administered the synthetic cannabinoid HU210 from postnatal days 35-48. Evidence of GBA activation was assessed in the hypothalamus, colon and fecal samples from male and female offspring at adolescence and adulthood Results: Findings were sex-specific with adolescent female offspring exhibiting an increased hypothalamic in-flammatory profile, increased hypothalamic CRHR1 mRNA, and decreased fecal expression of Bifidobacterium longum, however, no changes were detected in colonic inflammation or integrity. Conclusion: These results indicate that the rat two-hit model, documented to produce behavioural and neuroan-atomical abnormalities, also produces hypothalamic and microbiota abnormalities. The results also demonstrate significant sex differences, suggesting that this model may be useful for investigating the role of the GBA in the aetiology of neurodevelopmental disorders such as schizophrenia.
Background: Although the aetiology of schizophrenia remains unknown, it has been suggested that i... more Background: Although the aetiology of schizophrenia remains unknown, it has been suggested that it might occur in response to alterations in the gut-brain axis (GBA), the bi-directional communication system between the gut and the brain. The current study aimed to determine whether the "two-hit" animal model of neuro-psychopathology (maternal immune activation combined with adolescent cannabinoid exposure), produced abnormalities in the GBA Method: Pregnant Wistar rats were administered the viral mimetic polyI:C on gestational day 19 and offspring were administered the synthetic cannabinoid HU210 from postnatal days 35-48. Evidence of GBA activation was assessed in the hypothalamus, colon and fecal samples from male and female offspring at adolescence and adulthood Results: Findings were sex-specific with adolescent female offspring exhibiting an increased hypothalamic in-flammatory profile, increased hypothalamic CRHR1 mRNA, and decreased fecal expression of Bifidobacterium longum, however, no changes were detected in colonic inflammation or integrity. Conclusion: These results indicate that the rat two-hit model, documented to produce behavioural and neuroan-atomical abnormalities, also produces hypothalamic and microbiota abnormalities. The results also demonstrate significant sex differences, suggesting that this model may be useful for investigating the role of the GBA in the aetiology of neurodevelopmental disorders such as schizophrenia.
Abstract BPA 2021
Substance use disorder causes significant societal and social harm. Stress is... more Abstract BPA 2021
Substance use disorder causes significant societal and social harm. Stress is a common factor commonly linked with drug abuse at all phases of the addiction cycle. Corticotrophin-releasing hormone (CRH) neurons in the paraventricular nucleus of the hypothalamus (PVN) are highly responsive to stress and drugs, and control hormonal and behavioural responses to these stimuli. How PVN CRH neurons adapt to drug exposure and contribute to dysregulated stress reactivity is unclear.
Background: Anxiety disorders affect close to 10% of the world’s population, accounting for 30% o... more Background: Anxiety disorders affect close to 10% of the world’s population, accounting for 30% of the global non-fatal disease burden. Although their aetiology remains unknown, it has been suggested that anxiety disorders might occur in response to alterations in the gut-brain axis (GBA), the bi-directional communication system between the gut and the brain. The current study aimed to determine whether the well-characterized animal model of neuropsychopathology, the “two-hit model” (maternal infection combined with adolescent cannabinoid exposure), produced abnormalities in the GBA in association with anxiety-like behaviours.
Method: Pregnant Wistar rats were administered the viral mimetic PolyI:C on gestational day 19 and offspring were administered the synthetic cannabinoid HU210 from postnatal days 35–48. Evidence of GBA activation was assessed in the hypothalamus and fecal samples from offspring. Given anxiety disorders affect twice as many females as males, gender differences were also investigated.
Results: Male offspring exhibited no significant outcomes. Female offspring exhibited an increased hypothalamic inflammatory profile, increased hypothalamic CRHR1 mRNA, and decreased fecal expression of the anxiety-reducing bacteria Bifidobacterium longum, however, no anxiety-like behaviour was detected.
Conclusion: These results indicate that the rat two-hit model, well documented to produce behavioural and neuroanatomical abnormalities, also produces GBA disruptions. The results also demonstrate significant sex differences, suggesting that this model may be useful for investigating the role of the GBA in the aetiology of neurodevelopmental disorders.
Background:
Drug addictions is a complex neuropsychiatric disorder that causes significant socie... more Background: Drug addictions is a complex neuropsychiatric disorder that causes significant societal and personal harm. Current research suggests that drugs of abuse such as cocaine disrupt stress response pathways including the hypothalamic-pituitary-adrenal (HPA) axis. Altered HPA function is linked with abnormal responses to stress and is considered a key substrate withdrawal and relapse. The corticotrophin-releasing-hormone (CRH) cells of the paraventricular nucleus (PVN) strongly modulate the HPA axis, although it is currently unknown how they are influenced by cocaine. We applied electrophysiological and in vivo Ca2+ recording approaches to detect cocaine-induced changes in these PVN neurons. Methods: Male and female CRH-IRES-Cre::td-tomato mice received injections of cocaine (15mg/kg i.p.) or vehicle (saline) for 7-10 days. For electrophysiology experiments, one day later patch clamp recordings were made from TD-positive cells in the PVN (n=20 mice; n=85 cells). For photometry experiments, mice were injected with GCaMP6f in the PVN, followed by a fibre optic cannula. Seven days post cocaine administration stress- like behaviour was induced and assessed over two counterbalanced conditions: a robotic remote controlled bug or a looming shadow. Next, c-Fos immunohistochemistry was performed to assess stress reactivity in the PVN. Results: Compared to controls, an increase in mEPSC frequency and latency to first spike were observed in cocaine exposed animals. Cocaine also tended to increase the number of cells showing burst versus regular firing. Saline and cocaine exposed mice showed Ca2+ transients in response to the introduction of a robobug or a looming shadow. Cocaine exposed mice displayed pronounced stress-like behaviour in response to the looming shadow, such as hiding. Discussion: These results indicate that cocaine enhances excitatory drive to PVN CRH neurons. Moreover, an increased latency to first spike may result from adaptations in CRH neurons to limit drug-induced increases in CRH cell activity. Further work is currently underway to determine if these changes are linked with enhanced cellular and behavioural reactivity to stress.
Preferred Format: POSTER Background: Accumulating evidence suggests the psychopathology of anxiet... more Preferred Format: POSTER Background: Accumulating evidence suggests the psychopathology of anxiety involves the bi-directional relationship between the gastrointestinal (GI) tract and the brain, with GI abnormalities a significant co-morbidity of anxiety disorders. Maternal infection and adolescent cannabis exposure are two environmental risk factors that can lead to the development of an anxiety disorder. Using a rat model, we hypothesised that a combination of the two risk factors (two-hit) would produce GI inflammation and integrity disruptions in association with anxiety-like behaviour. Methods: Pregnant Wistar rats were exposed to polyI:C or saline on gestational day 19. On postnatal day (PND) 35 offspring received daily injections of the synthetic cannabinoid HU210 or control for 14 days. Gut and brain tissue was collected on PND 50 (adolescence) and PND 90 (adulthood). Molecular analyses were performed to assess GI inflammation and integrity. Adult offspring (PND 100) were tested for anxiety-like behavior using elevated plus maze and Ethovision XT TM software. Results: Initial results indicate that in comparison to controls, two-hit PND 50 male and female offspring have a decreased inflammatory response in the colon and PND 50 male offspring display evidence of altered GI integrity. No inflammatory or GI abnormalities were detected in PND 90 offspring. Both male and female adult offspring exhibited no evidence of anxiety-like behaviour, however, male offspring showed a significant latency to enter the open arms of the elevated plus maze, indicative of avoidance or perhaps altered goal-directed and motivated behaviour. Conclusion: The preliminary results suggest that combination of the two risk factors decreases intestinal inflammation and induces subtle alterations in GI integrity, but does not produce overt anxiety-like behaviour. Interestingly, there were sex and age differences in these responses. Given these results, this research indicates that this animal model may not be useful to study the underlying mechanisms of anxiety disorders.
Background: Anxiety disorders affect close to 10% of the world’s population, accounting for 30% o... more Background: Anxiety disorders affect close to 10% of the world’s population, accounting for 30% of the global non-fatal disease burden. Although their aetiology remains unknown, it has been suggested that anxiety disorders might occur in response to alterations in the gut-brain axis (GBA), the bi-directional communication system between the gut and the brain. The current study aimed to determine whether the well-characterized animal model of neuropsychopathology, the “two-hit model” (maternal infection combined with adolescent cannabinoid exposure), produced abnormalities in the GBA in association with anxiety-like behaviours. Method: Pregnant Wistar rats were administered the viral mimetic PolyI:C on gestational day 19 and offspring were administered the synthetic cannabinoid HU210 from postnatal days 35–48. Evidence of GBA activation was assessed in the hypothalamus and fecal samples from offspring. Given anxiety disorders affect twice as many females as males, gender differences were also investigated. Results: Male offspring exhibited no significant outcomes. Female offspring exhibited an increased hypothalamic inflammatory profile, increased hypothalamic CRHR1 mRNA, and decreased fecal expression of the anxiety-reducing bacteria Bifidobacterium longum, however, no anxiety-like behaviour was detected. Conclusion: These results indicate that the rat two-hit model, well documented to produce behavioural and neuroanatomical abnormalities, also produces GBA disruptions. The results also demonstrate significant sex differences, suggesting that this model may be useful for investigating the role of the GBA in the aetiology of neurodevelopmental disorders.
Background: Anxiety disorders affect close to 10% of the world’s population, accounting for 30% o... more Background: Anxiety disorders affect close to 10% of the world’s population, accounting for 30% of the global non-fatal disease burden. Although their aetiology remains unknown, it has been suggested that anxiety disorders might occur in response to alterations in the gut-brain axis (GBA), the bi-directional communication system between the gut and the brain. The current study aimed to determine whether the well-characterized animal model of neuropsychopathology, the “two-hit model” (maternal infection combined with adolescent cannabinoid exposure), produced abnormalities in the GBA in association with anxiety-like behaviours. Method: Pregnant Wistar rats were administered the viral mimetic PolyI:C on gestational day 19 and offspring were administered the synthetic cannabinoid HU210 from postnatal days 35–48. Evidence of GBA activation was assessed in the hypothalamus and fecal samples from offspring. Given anxiety disorders affect twice as many females as males, gender differences ...
Background: Although the aetiology of schizophrenia remains unknown, it has been suggested that i... more Background: Although the aetiology of schizophrenia remains unknown, it has been suggested that it might occur in response to alterations in the gut-brain axis (GBA), the bi-directional communication system between the gut and the brain. The current study aimed to determine whether the "two-hit" animal model of neuro-psychopathology (maternal immune activation combined with adolescent cannabinoid exposure), produced abnormalities in the GBA Method: Pregnant Wistar rats were administered the viral mimetic polyI:C on gestational day 19 and offspring were administered the synthetic cannabinoid HU210 from postnatal days 35-48. Evidence of GBA activation was assessed in the hypothalamus, colon and fecal samples from male and female offspring at adolescence and adulthood Results: Findings were sex-specific with adolescent female offspring exhibiting an increased hypothalamic in-flammatory profile, increased hypothalamic CRHR1 mRNA, and decreased fecal expression of Bifidobacterium longum, however, no changes were detected in colonic inflammation or integrity. Conclusion: These results indicate that the rat two-hit model, documented to produce behavioural and neuroan-atomical abnormalities, also produces hypothalamic and microbiota abnormalities. The results also demonstrate significant sex differences, suggesting that this model may be useful for investigating the role of the GBA in the aetiology of neurodevelopmental disorders such as schizophrenia.
Background: Although the aetiology of schizophrenia remains unknown, it has been suggested that i... more Background: Although the aetiology of schizophrenia remains unknown, it has been suggested that it might occur in response to alterations in the gut-brain axis (GBA), the bi-directional communication system between the gut and the brain. The current study aimed to determine whether the "two-hit" animal model of neuro-psychopathology (maternal immune activation combined with adolescent cannabinoid exposure), produced abnormalities in the GBA Method: Pregnant Wistar rats were administered the viral mimetic polyI:C on gestational day 19 and offspring were administered the synthetic cannabinoid HU210 from postnatal days 35-48. Evidence of GBA activation was assessed in the hypothalamus, colon and fecal samples from male and female offspring at adolescence and adulthood Results: Findings were sex-specific with adolescent female offspring exhibiting an increased hypothalamic in-flammatory profile, increased hypothalamic CRHR1 mRNA, and decreased fecal expression of Bifidobacterium longum, however, no changes were detected in colonic inflammation or integrity. Conclusion: These results indicate that the rat two-hit model, documented to produce behavioural and neuroan-atomical abnormalities, also produces hypothalamic and microbiota abnormalities. The results also demonstrate significant sex differences, suggesting that this model may be useful for investigating the role of the GBA in the aetiology of neurodevelopmental disorders such as schizophrenia.
Abstract BPA 2021
Substance use disorder causes significant societal and social harm. Stress is... more Abstract BPA 2021
Substance use disorder causes significant societal and social harm. Stress is a common factor commonly linked with drug abuse at all phases of the addiction cycle. Corticotrophin-releasing hormone (CRH) neurons in the paraventricular nucleus of the hypothalamus (PVN) are highly responsive to stress and drugs, and control hormonal and behavioural responses to these stimuli. How PVN CRH neurons adapt to drug exposure and contribute to dysregulated stress reactivity is unclear.
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Method: Pregnant Wistar rats were administered the viral mimetic PolyI:C on gestational day 19 and offspring were administered the synthetic cannabinoid HU210 from postnatal days 35–48. Evidence of GBA activation was assessed in the hypothalamus and fecal samples from offspring. Given anxiety disorders affect twice as many females as males, gender differences were also investigated.
Results: Male offspring exhibited no significant outcomes. Female offspring exhibited an increased hypothalamic inflammatory profile, increased hypothalamic CRHR1 mRNA, and decreased fecal expression of the anxiety-reducing bacteria Bifidobacterium longum, however, no anxiety-like behaviour was detected.
Conclusion: These results indicate that the rat two-hit model, well documented to produce behavioural and neuroanatomical abnormalities, also produces GBA disruptions. The results also demonstrate significant sex differences, suggesting that this model may be useful for investigating the role of the GBA in the aetiology of neurodevelopmental disorders.
Drug addictions is a complex neuropsychiatric disorder that causes significant societal and personal harm.
Current research suggests that drugs of abuse such as cocaine disrupt stress response pathways including
the hypothalamic-pituitary-adrenal (HPA) axis. Altered HPA function is linked with abnormal responses to
stress and is considered a key substrate withdrawal and relapse. The corticotrophin-releasing-hormone
(CRH) cells of the paraventricular nucleus (PVN) strongly modulate the HPA axis, although it is currently
unknown how they are influenced by cocaine. We applied electrophysiological and in vivo Ca2+ recording
approaches to detect cocaine-induced changes in these PVN neurons.
Methods:
Male and female CRH-IRES-Cre::td-tomato mice received injections of cocaine (15mg/kg i.p.) or vehicle
(saline) for 7-10 days. For electrophysiology experiments, one day later patch clamp recordings were made
from TD-positive cells in the PVN (n=20 mice; n=85 cells). For photometry experiments, mice were injected
with GCaMP6f in the PVN, followed by a fibre optic cannula. Seven days post cocaine administration stress-
like behaviour was induced and assessed over two counterbalanced conditions: a robotic remote controlled
bug or a looming shadow. Next, c-Fos immunohistochemistry was performed to assess stress reactivity in
the PVN.
Results:
Compared to controls, an increase in mEPSC frequency and latency to first spike were observed in cocaine
exposed animals. Cocaine also tended to increase the number of cells showing burst versus regular firing.
Saline and cocaine exposed mice showed Ca2+ transients in response to the introduction of a robobug or a
looming shadow. Cocaine exposed mice displayed pronounced stress-like behaviour in response to the
looming shadow, such as hiding.
Discussion:
These results indicate that cocaine enhances excitatory drive to PVN CRH neurons. Moreover, an increased
latency to first spike may result from adaptations in CRH neurons to limit drug-induced increases in CRH cell
activity. Further work is currently underway to determine if these changes are linked with enhanced
cellular and behavioural reactivity to stress.
Substance use disorder causes significant societal and social harm. Stress is a common factor commonly linked with drug abuse at all phases of the addiction cycle. Corticotrophin-releasing hormone (CRH) neurons in the paraventricular nucleus of the hypothalamus (PVN) are highly responsive to stress and drugs, and control hormonal and behavioural responses to these stimuli. How PVN CRH neurons adapt to drug exposure and contribute to dysregulated stress reactivity is unclear.
Method: Pregnant Wistar rats were administered the viral mimetic PolyI:C on gestational day 19 and offspring were administered the synthetic cannabinoid HU210 from postnatal days 35–48. Evidence of GBA activation was assessed in the hypothalamus and fecal samples from offspring. Given anxiety disorders affect twice as many females as males, gender differences were also investigated.
Results: Male offspring exhibited no significant outcomes. Female offspring exhibited an increased hypothalamic inflammatory profile, increased hypothalamic CRHR1 mRNA, and decreased fecal expression of the anxiety-reducing bacteria Bifidobacterium longum, however, no anxiety-like behaviour was detected.
Conclusion: These results indicate that the rat two-hit model, well documented to produce behavioural and neuroanatomical abnormalities, also produces GBA disruptions. The results also demonstrate significant sex differences, suggesting that this model may be useful for investigating the role of the GBA in the aetiology of neurodevelopmental disorders.
Drug addictions is a complex neuropsychiatric disorder that causes significant societal and personal harm.
Current research suggests that drugs of abuse such as cocaine disrupt stress response pathways including
the hypothalamic-pituitary-adrenal (HPA) axis. Altered HPA function is linked with abnormal responses to
stress and is considered a key substrate withdrawal and relapse. The corticotrophin-releasing-hormone
(CRH) cells of the paraventricular nucleus (PVN) strongly modulate the HPA axis, although it is currently
unknown how they are influenced by cocaine. We applied electrophysiological and in vivo Ca2+ recording
approaches to detect cocaine-induced changes in these PVN neurons.
Methods:
Male and female CRH-IRES-Cre::td-tomato mice received injections of cocaine (15mg/kg i.p.) or vehicle
(saline) for 7-10 days. For electrophysiology experiments, one day later patch clamp recordings were made
from TD-positive cells in the PVN (n=20 mice; n=85 cells). For photometry experiments, mice were injected
with GCaMP6f in the PVN, followed by a fibre optic cannula. Seven days post cocaine administration stress-
like behaviour was induced and assessed over two counterbalanced conditions: a robotic remote controlled
bug or a looming shadow. Next, c-Fos immunohistochemistry was performed to assess stress reactivity in
the PVN.
Results:
Compared to controls, an increase in mEPSC frequency and latency to first spike were observed in cocaine
exposed animals. Cocaine also tended to increase the number of cells showing burst versus regular firing.
Saline and cocaine exposed mice showed Ca2+ transients in response to the introduction of a robobug or a
looming shadow. Cocaine exposed mice displayed pronounced stress-like behaviour in response to the
looming shadow, such as hiding.
Discussion:
These results indicate that cocaine enhances excitatory drive to PVN CRH neurons. Moreover, an increased
latency to first spike may result from adaptations in CRH neurons to limit drug-induced increases in CRH cell
activity. Further work is currently underway to determine if these changes are linked with enhanced
cellular and behavioural reactivity to stress.
Substance use disorder causes significant societal and social harm. Stress is a common factor commonly linked with drug abuse at all phases of the addiction cycle. Corticotrophin-releasing hormone (CRH) neurons in the paraventricular nucleus of the hypothalamus (PVN) are highly responsive to stress and drugs, and control hormonal and behavioural responses to these stimuli. How PVN CRH neurons adapt to drug exposure and contribute to dysregulated stress reactivity is unclear.