Sjoukje Kuipers - Academia.edu (original) (raw)

Papers by Sjoukje Kuipers

Neuropharmacology, Jan 1, 2006

Affective disorders are common psychiatric illnesses characterized by marked gender-related preva... more Affective disorders are common psychiatric illnesses characterized by marked gender-related prevalence. Recent evidence links chronic stress and dysregulation of neurotrophin signaling with the development of depression, while novel theories suggest that antidepressants may act by promoting intracellular adaptations linked to neuroplasticity. Although selective serotonin reuptake inhibitors (SSRIs) efficaciously improve a variety of dysfunctions in males, their neuroendocrine effects and intracellular signaling patterns in females are not well determined. Here we show that chronic footshock stress (21 days) promotes HPA axis hyperactivity (as seen by the increased FOS-ir in the paraventricular hypothalamic nucleus (PVN), plasma corticosterone and adrenal hypertrophy), reduces hippocampal BrdU immunoreactivity and suppresses cortical–limbic CREB phosphorylation in female rats. Long-term citalopram treatment, in contrast, attenuates stress-induced elevation of corticosterone levels and adrenal hypertrophy, although it does not reverse footshock-mediated induction of FOS-ir in the PVN, inhibition of CREB phosphorylation and reduction of hippocampal BrdU-labeling. Moreover, citalopram administration was also associated with significant hypophagic effects and inhibition of CREB phosphorylation. These data suggest that, in female rats, normalization of chronic stress-induced HPA axis abnormalities may represent an initial phase of citalopram-mediated therapeutic actions and despite this SSRI's apparent lack of effects on neuroplasticity, we cannot exclude the possibility that some neurochemical adaptations occur in a later stage which may require more than 3 weeks of treatment to manifest.

Physiology & Behavior, 2008

Social defeat, resulting from the fight for a territory is based on the resident–intruder paradig... more Social defeat, resulting from the fight for a territory is based on the resident–intruder paradigm. A male rat intruder is placed in the territory of an older, bigger and more aggressive male resident and is defeated. In the present study, a double exposure to social defeat increased sleep fragmentation due to an increased amount of waking and slow-wave-sleep-1 (SWS-1) episodes. Also, social defeats increased the amount of slow-wave-sleep-2 (SWS-2). In repeated exposures to an open field, socially defeated rats showed low central activity and persistent defecation indicating high emotionality. The strongest effects of social defeat on sleep and open field behaviour were seen sub-chronically after stress. Social defeat did not induce changes in rapid eye movement (REM) sleep (e.g. total amount, latency), sleep latency, sexual activity, body weight or adrenal weight. A negative correlation between habituation in open field central activity and total sleep fragmentation indicates a commonality of effects of social defeat on both behaviour and sleep.

Current opinion in drug discovery & development, 2006

Synaptic plasticity, the fiundamental ability of synapses to undergo experience-dependent changes... more Synaptic plasticity, the fiundamental ability of synapses to undergo experience-dependent changes in synaptic strength, is thought to underlie a range of long-term adaptive responses of the central nervous system. The inability to generate or maintain appropriate changes in synaptic connectivity and neuronal circuitry is likely to impair cognitive futnction associated with many neurological and psychiatric disorders. The success of intervening therapeutic approaches will depend on the ability to target key component mechanisms in the complex process of synaptic plasticity. Brain-derived neurotrophic factor (BDNF) has emerged as a major regulator of synaptic plasticity and a key target in disorders such as major depression and Alzheimner's disease. This review discusses findings that link BDNF mechanisms in synaptic plasticity to disease mechanisms and possible future therapies.

Progress in neuro-psychopharmacology & biological psychiatry, 2003

Stress plays an important role in the development of affective disorders. Women show a higher pre... more Stress plays an important role in the development of affective disorders. Women show a higher prevalence for these disorders than men. The course of a depression is thought to be positively influenced by social support. The authors have used a chronic mild stress model in which rats received footshocks daily for 3 weeks. Since rats are social animals we hypothesized that "social support" might reduce the adverse effects of chronic stress. To test this hypothesis, male and female rats were housed individually or socially in unisex groups of four rats. An open field test was repeated four times during the 3 weeks of treatment. Neuronal activation in the paraventricular nucleus of the hypothalamus (PVN) and dorsal raphe nucleus (DRN) in response to stress was measured the last day with c-fos. Chronic stress exposure increased locomotor activity in the open field, especially during the first minute. This was most pronounced in the individually housed females. In females, socia...

Neurobiology of Aging, 2015

Adult hippocampal neurogenesis drastically diminishes with age but the underlying mechanisms rema... more Adult hippocampal neurogenesis drastically diminishes with age but the underlying mechanisms remain unclear. Here, age-related influences on the hippocampal early neuroprogenitor cell (NPC) pool was examined by quantifying changes in Sox1-expressing cells in the dentate gyrus subgranular zone from early adulthood (3 months) to middle age (12 months). Proliferation of distinct NPC subpopulations (Sox1þ, Nestinþ, and Doublecortinþ) and newborn cell survival were also investigated. Examination of total 5-bromodeoxyuridine (BrdU)þ and Doublecortin (DCX)AE cells revealed an early and dramatic agedependent decline of hippocampal neurogenesis. Increasing age from 3 to 12 months was primarily associated with reduced total proliferation, in vivo (À79% of BrdUþ cells) but not in vitro, and DCXþ cell numbers (À89%). When proliferative rates of individual NPC subpopulations were examined, a different picture emerged as proliferating Nestinþ neuroprogenitors (À95% at 9 months) and BrdUþ/DCXþ neuroblasts and/or immature neurons (À83% at 12 months) declined the most, whereas proliferating Sox1þ NPCs only dropped by 53%. Remarkably, despite greatly reduced proliferative rates and recent reports of Nestinþ neuroprogenitor loss, total numbers of early Sox1þ NPCs were unaffected by age (at least up to middle age), and newborn cell survival within the dentate gyrus was increased. Neuronal differentiation was concomitantly reduced; however, thus suggesting age-associated changes in fatechoice determination.

BACKGROUND: Developmental, physiological and tissue engineering studies critical to the developme... more BACKGROUND: Developmental, physiological and tissue engineering studies critical to the development of successful myocardial regeneration therapies require new ways to effectively visualize and isolate large numbers of fluorescently labeled, functional ...

PLoS ONE, 2009

Progenitor cells in the adult dentate gyrus provide a constant supply of neuronal precursors, yet... more Progenitor cells in the adult dentate gyrus provide a constant supply of neuronal precursors, yet only a small fraction of these cells survive and develop into mature dentate granule cells (DGCs). A major challenge of current research is thus to understand the stringent selection process that governs the maturation and functional integration of adult-born DGCs. In mature DGCs, high-frequency stimulation (HFS) of the perforant path input elicits robust expression of the immediate early gene Arc/Arg3.1, trafficking of its mRNA to dendrites, and local synthesis of the protein necessary for consolidation of longterm potentiation (LTP). Given the synaptic commitment inherent in LTP consolidation, we considered that HFS-evoked expression of Arc could be used to timemap the functional integration of newborn DGCs. Dividing cells were birthmarked by BrdU-labeling at 1, 7, 14, 21, or 28 days prior to induction of LTP and expression of Arc was examined by confocal microscopy. Contrary to expectation, LTP did not induce Arc expression in newborn cells at any age, suggesting they might be refractory to synaptically-evoked Arc expression for at least one month. Importantly, however, spontaneous expression of Arc was detected in BrdU-labeled cells and strongly associated with the survival and maturation of NeuN-positive DGCs. Moreover, Arc expression at the earliest ages (1 and 7 days), clearly precedes the formation of glutamatergic synapses on new neurons. These results suggest an unexpected early role for Arc in adult-born DGCs, distinct from its functions in LTP, LTD, and homeostatic synaptic plasticity.

Neuropharmacology, 2013

Growing evidence suggests neuroplasticity changes are pivotal in both the occurrence and treatmen... more Growing evidence suggests neuroplasticity changes are pivotal in both the occurrence and treatment of affective disorders. Abnormal expression and/or phosphorylation of numerous plasticity-related proteins have been observed in depression, while prolonged antidepressant treatment has been associated with the attenuation of stress-mediated effects on dendritic remodeling and adult hippocampal neurogenesis in experimental animals. This study explores the neurobiological adaptations induced by chronic stress and/or long-term tianeptine treatment. Male and female rats were studied to determine the potential contributory role of sex differences on stress-induced pathology and antidepressant-mediated actions. Our results confirm chronic stress-induced HPA axis disturbance and neuroplasticity impairment in both sexes (i.e. reduced CREB phosphorylation and hippocampal BrdU labeling). Commonly ensuing neurobiological alterations were accompanied by unique sex-specific adaptations. When the antidepressant tianeptine was administered, HPA axis hyperactivity was attenuated and specific neuronal defects were ameliorated in both sexes. These findings provide novel insight into sex-related influences on the neurobiological substrates mediating chronic stress-induced actions on neuroplasticity and the mechanisms underlying tianeptine-mediated therapeutic effects.

Neuropharmacology, 2006

Affective disorders are common psychiatric illnesses characterized by marked gender-related preva... more Affective disorders are common psychiatric illnesses characterized by marked gender-related prevalence. Recent evidence links chronic stress and dysregulation of neurotrophin signaling with the development of depression, while novel theories suggest that antidepressants may act by promoting intracellular adaptations linked to neuroplasticity. Although selective serotonin reuptake inhibitors (SSRIs) efficaciously improve a variety of dysfunctions in males, their neuroendocrine effects and intracellular signaling patterns in females are not well determined.

Journal of Neurochemistry, 2003

Disturbed adaptations at the molecular and cellular levels following stress could represent compr... more Disturbed adaptations at the molecular and cellular levels following stress could represent compromised neural plasticity that contributes to the pathophysiology of stress-induced disorders. Evidence illustrates atrophy and cell death of stress-vulnerable neurones in the prefrontal cortex. Reduced plasticity may be realized through the destabilized function of selective proteins involved in organizing the neuronal skeleton and translating neurotrophic signals. To elucidate the mechanisms underlying these effects, rats were exposed to chronic footshock stress. Patterns of c-fos, phospho-extracellularregulated protein kinases 1/2 (ERK1/2), calcineurin and phospho-cyclic-AMP response-element binding protein (CREB) expression were subsequently investigated. The results indicate chronic stress-induced impairments in prefrontal and cingulate signal transduction cascades underlying neuronal plasticity. The medial prefrontal cortex, demonstrated functional hyperactivity and dendritic phospho-ERK1/2 hyperphosphorylation, while reduced c-fos and calcineurin immunoreactivity occurred in the cingulate cortex. Significantly reduced phospho-CREB expression in both cortical regions, considering its implication in brain-derived neurotrophic factor (BDNF) transcription, suggests reduced synaptic plasticity. This data confirms the damaging effect of stress on cortical activity, on a molecular level. Due to the association of these markers in the regulation of BDNF signalling, these findings suggest a central role for intracellular neurotrophin transduction members in the pathways underlying cellular actions of stress in the brain.

Experimental Brain Research, 2010

The immediate early gene Arc is emerging as a versatile, Wnely tuned system capable of coupling c... more The immediate early gene Arc is emerging as a versatile, Wnely tuned system capable of coupling changes in neuronal activity patterns to synaptic plasticity, thereby optimizing information storage in the nervous system. Here, we attempt to overview the Arc system spanning from transcriptional regulation of the Arc gene, to dendritic transport, metabolism, and translation of Arc mRNA, to post-translational modiWcation, localization, and degradation of Arc protein. Within this framework we discuss the function of Arc in regulation of actin cytoskeletal dynamics underlying consolidation of long-term potentiation (LTP) and regulation of AMPA-type glutamate receptor endocytosis underlying long-term depression (LTD) and homeostatic plasticity. Behaviorally, Arc has a key role in consolidation of explicit and implicit forms of memory, with recent work implicating Arc in adaptation to stress as well as maladaptive plasticity connected to drug addiction. Arc holds considerable promise as a "master regulator" of protein synthesis-dependent forms of synaptic plasticity, but the mechanisms that modulate and switch Arc function are only beginning to be elucidated.

European Journal of Neuroscience, 2002

Stress has been shown to affect brain structural plasticity, promote long-term changes in multipl... more Stress has been shown to affect brain structural plasticity, promote long-term changes in multiple neurotransmitter systems and cause neuronal atrophy. However, the mechanisms involved in these stress-related neural alterations are still poorly understood. Mitogen-activated protein kinase (MAPK) cascades play a crucial role in the transduction of neurotrophic signal from the cell surface to the nucleus and are implicated in the modulation of synaptic plasticity and neuronal survival. An intriguing possibility is that stress might in¯uence brain plasticity through its effects on selective members of such intracellular signalling cascades responsible for the transduction of neurotrophin signals. Here, we have investigated the effects of stress on the expression of three members of the MAPK/extracellular-regulated kinase (ERK) pathway such as phospho-ERK1, phospho-ERK2 and phospho-cAMP/calcium-responsive element-binding protein (CREB) in the adult rat brain. Male rats were subjected to mild footshocks and the patterns of protein expression were analysed after 21 consecutive days of stress. We found that chronic stress induced a pronounced and persistent ERK1/2 hyperphosphorylation in dendrites of the higher prefrontocortical layers (II and III) and a reduction of phospho-CREB expression in several cortical and subcortical regions. We hypothesized that defects in ERK signalling regulation combined with a reduced phospho-CREB activity may be a crucial mechanism by which sustained stress may induce atrophy of selective subpopulations of vulnerable cortical neurons and/or distal dendrites. Thus, ERK-mediated cortical abnormalities may represent a speci®c path by which chronic stress affects the functioning of cortical structures and causes selective neural network defects.

European Journal of Neuroscience, 2006

The delayed therapeutic onset observed in response to chronic antidepressant drug treatment is li... more The delayed therapeutic onset observed in response to chronic antidepressant drug treatment is little understood. While current theories emphasize effects on gene transcription, possible effects of antidepressant drugs on translation control pathways have not been explored. We examined the effect of the selective serotonergic reuptake inhibitor fluoxetine on regulation of two major determinants of mRNA translation, eukaryotic initiation factor 4E (eIF4E) and eukaryotic elongation factor 2 (eEF2). Chronic fluoxetine treatment induced hyperphosphorylation of eEF2 (Thr56) in prefrontal cortex, hippocampus and dentate gyrus of rats. By contrast, phosphorylation of eIF4E (Ser209) was observed specifically in the dentate gyrus. Acute fluoxetine treatment had no effect on translational factor activity. These findings suggest that region-specific regulation of translation contributes to the delayed action of antidepressant drugs such as fluoxetine.

The monoamine hypothesis of depression was coined over 30 years ago [1, 2]. This hypothesis propo... more The monoamine hypothesis of depression was coined over 30 years ago [1, 2]. This hypothesis proposes that there is an underlying biological basis for depression, namely a deficiency of the monoamine neurotransmitters norepinephrine, serotonin, and/or ...

Physiology & Behavior, 2008

Social defeat, resulting from the fight for a territory is based on the resident-intruder paradig... more Social defeat, resulting from the fight for a territory is based on the resident-intruder paradigm. A male rat intruder is placed in the territory of an older, bigger and more aggressive male resident and is defeated. In the present study, a double exposure to social defeat increased sleep fragmentation due to an increased amount of waking and slow-wave-sleep-1 (SWS-1) episodes. Also, social defeat increased the amount of slow-wave-sleep-2 (SWS-2). In repeated exposures to an open field, socially defeated rats showed low central activity and persistent defecation indicating high emotionality. The strongest effects of social defeat on sleep and open field behaviour were seen sub-chronically after stress. Social defeat did not induce changes in rapid eye movement (REM) sleep (e.g. total amount, latency), sleep latency, sexual activity, body weight or adrenal weight. A negative correlation between habituation in open field central activity and total sleep fragmentation indicates a commonality of effects of social defeat on both behaviour and sleep.

Neuropharmacology, Jan 1, 2006

Affective disorders are common psychiatric illnesses characterized by marked gender-related preva... more Affective disorders are common psychiatric illnesses characterized by marked gender-related prevalence. Recent evidence links chronic stress and dysregulation of neurotrophin signaling with the development of depression, while novel theories suggest that antidepressants may act by promoting intracellular adaptations linked to neuroplasticity. Although selective serotonin reuptake inhibitors (SSRIs) efficaciously improve a variety of dysfunctions in males, their neuroendocrine effects and intracellular signaling patterns in females are not well determined. Here we show that chronic footshock stress (21 days) promotes HPA axis hyperactivity (as seen by the increased FOS-ir in the paraventricular hypothalamic nucleus (PVN), plasma corticosterone and adrenal hypertrophy), reduces hippocampal BrdU immunoreactivity and suppresses cortical–limbic CREB phosphorylation in female rats. Long-term citalopram treatment, in contrast, attenuates stress-induced elevation of corticosterone levels and adrenal hypertrophy, although it does not reverse footshock-mediated induction of FOS-ir in the PVN, inhibition of CREB phosphorylation and reduction of hippocampal BrdU-labeling. Moreover, citalopram administration was also associated with significant hypophagic effects and inhibition of CREB phosphorylation. These data suggest that, in female rats, normalization of chronic stress-induced HPA axis abnormalities may represent an initial phase of citalopram-mediated therapeutic actions and despite this SSRI's apparent lack of effects on neuroplasticity, we cannot exclude the possibility that some neurochemical adaptations occur in a later stage which may require more than 3 weeks of treatment to manifest.

Physiology & Behavior, 2008

Social defeat, resulting from the fight for a territory is based on the resident–intruder paradig... more Social defeat, resulting from the fight for a territory is based on the resident–intruder paradigm. A male rat intruder is placed in the territory of an older, bigger and more aggressive male resident and is defeated. In the present study, a double exposure to social defeat increased sleep fragmentation due to an increased amount of waking and slow-wave-sleep-1 (SWS-1) episodes. Also, social defeats increased the amount of slow-wave-sleep-2 (SWS-2). In repeated exposures to an open field, socially defeated rats showed low central activity and persistent defecation indicating high emotionality. The strongest effects of social defeat on sleep and open field behaviour were seen sub-chronically after stress. Social defeat did not induce changes in rapid eye movement (REM) sleep (e.g. total amount, latency), sleep latency, sexual activity, body weight or adrenal weight. A negative correlation between habituation in open field central activity and total sleep fragmentation indicates a commonality of effects of social defeat on both behaviour and sleep.

Current opinion in drug discovery & development, 2006

Synaptic plasticity, the fiundamental ability of synapses to undergo experience-dependent changes... more Synaptic plasticity, the fiundamental ability of synapses to undergo experience-dependent changes in synaptic strength, is thought to underlie a range of long-term adaptive responses of the central nervous system. The inability to generate or maintain appropriate changes in synaptic connectivity and neuronal circuitry is likely to impair cognitive futnction associated with many neurological and psychiatric disorders. The success of intervening therapeutic approaches will depend on the ability to target key component mechanisms in the complex process of synaptic plasticity. Brain-derived neurotrophic factor (BDNF) has emerged as a major regulator of synaptic plasticity and a key target in disorders such as major depression and Alzheimner's disease. This review discusses findings that link BDNF mechanisms in synaptic plasticity to disease mechanisms and possible future therapies.

Progress in neuro-psychopharmacology & biological psychiatry, 2003

Stress plays an important role in the development of affective disorders. Women show a higher pre... more Stress plays an important role in the development of affective disorders. Women show a higher prevalence for these disorders than men. The course of a depression is thought to be positively influenced by social support. The authors have used a chronic mild stress model in which rats received footshocks daily for 3 weeks. Since rats are social animals we hypothesized that "social support" might reduce the adverse effects of chronic stress. To test this hypothesis, male and female rats were housed individually or socially in unisex groups of four rats. An open field test was repeated four times during the 3 weeks of treatment. Neuronal activation in the paraventricular nucleus of the hypothalamus (PVN) and dorsal raphe nucleus (DRN) in response to stress was measured the last day with c-fos. Chronic stress exposure increased locomotor activity in the open field, especially during the first minute. This was most pronounced in the individually housed females. In females, socia...

Neurobiology of Aging, 2015

Adult hippocampal neurogenesis drastically diminishes with age but the underlying mechanisms rema... more Adult hippocampal neurogenesis drastically diminishes with age but the underlying mechanisms remain unclear. Here, age-related influences on the hippocampal early neuroprogenitor cell (NPC) pool was examined by quantifying changes in Sox1-expressing cells in the dentate gyrus subgranular zone from early adulthood (3 months) to middle age (12 months). Proliferation of distinct NPC subpopulations (Sox1þ, Nestinþ, and Doublecortinþ) and newborn cell survival were also investigated. Examination of total 5-bromodeoxyuridine (BrdU)þ and Doublecortin (DCX)AE cells revealed an early and dramatic agedependent decline of hippocampal neurogenesis. Increasing age from 3 to 12 months was primarily associated with reduced total proliferation, in vivo (À79% of BrdUþ cells) but not in vitro, and DCXþ cell numbers (À89%). When proliferative rates of individual NPC subpopulations were examined, a different picture emerged as proliferating Nestinþ neuroprogenitors (À95% at 9 months) and BrdUþ/DCXþ neuroblasts and/or immature neurons (À83% at 12 months) declined the most, whereas proliferating Sox1þ NPCs only dropped by 53%. Remarkably, despite greatly reduced proliferative rates and recent reports of Nestinþ neuroprogenitor loss, total numbers of early Sox1þ NPCs were unaffected by age (at least up to middle age), and newborn cell survival within the dentate gyrus was increased. Neuronal differentiation was concomitantly reduced; however, thus suggesting age-associated changes in fatechoice determination.

BACKGROUND: Developmental, physiological and tissue engineering studies critical to the developme... more BACKGROUND: Developmental, physiological and tissue engineering studies critical to the development of successful myocardial regeneration therapies require new ways to effectively visualize and isolate large numbers of fluorescently labeled, functional ...

PLoS ONE, 2009

Progenitor cells in the adult dentate gyrus provide a constant supply of neuronal precursors, yet... more Progenitor cells in the adult dentate gyrus provide a constant supply of neuronal precursors, yet only a small fraction of these cells survive and develop into mature dentate granule cells (DGCs). A major challenge of current research is thus to understand the stringent selection process that governs the maturation and functional integration of adult-born DGCs. In mature DGCs, high-frequency stimulation (HFS) of the perforant path input elicits robust expression of the immediate early gene Arc/Arg3.1, trafficking of its mRNA to dendrites, and local synthesis of the protein necessary for consolidation of longterm potentiation (LTP). Given the synaptic commitment inherent in LTP consolidation, we considered that HFS-evoked expression of Arc could be used to timemap the functional integration of newborn DGCs. Dividing cells were birthmarked by BrdU-labeling at 1, 7, 14, 21, or 28 days prior to induction of LTP and expression of Arc was examined by confocal microscopy. Contrary to expectation, LTP did not induce Arc expression in newborn cells at any age, suggesting they might be refractory to synaptically-evoked Arc expression for at least one month. Importantly, however, spontaneous expression of Arc was detected in BrdU-labeled cells and strongly associated with the survival and maturation of NeuN-positive DGCs. Moreover, Arc expression at the earliest ages (1 and 7 days), clearly precedes the formation of glutamatergic synapses on new neurons. These results suggest an unexpected early role for Arc in adult-born DGCs, distinct from its functions in LTP, LTD, and homeostatic synaptic plasticity.

Neuropharmacology, 2013

Growing evidence suggests neuroplasticity changes are pivotal in both the occurrence and treatmen... more Growing evidence suggests neuroplasticity changes are pivotal in both the occurrence and treatment of affective disorders. Abnormal expression and/or phosphorylation of numerous plasticity-related proteins have been observed in depression, while prolonged antidepressant treatment has been associated with the attenuation of stress-mediated effects on dendritic remodeling and adult hippocampal neurogenesis in experimental animals. This study explores the neurobiological adaptations induced by chronic stress and/or long-term tianeptine treatment. Male and female rats were studied to determine the potential contributory role of sex differences on stress-induced pathology and antidepressant-mediated actions. Our results confirm chronic stress-induced HPA axis disturbance and neuroplasticity impairment in both sexes (i.e. reduced CREB phosphorylation and hippocampal BrdU labeling). Commonly ensuing neurobiological alterations were accompanied by unique sex-specific adaptations. When the antidepressant tianeptine was administered, HPA axis hyperactivity was attenuated and specific neuronal defects were ameliorated in both sexes. These findings provide novel insight into sex-related influences on the neurobiological substrates mediating chronic stress-induced actions on neuroplasticity and the mechanisms underlying tianeptine-mediated therapeutic effects.

Neuropharmacology, 2006

Affective disorders are common psychiatric illnesses characterized by marked gender-related preva... more Affective disorders are common psychiatric illnesses characterized by marked gender-related prevalence. Recent evidence links chronic stress and dysregulation of neurotrophin signaling with the development of depression, while novel theories suggest that antidepressants may act by promoting intracellular adaptations linked to neuroplasticity. Although selective serotonin reuptake inhibitors (SSRIs) efficaciously improve a variety of dysfunctions in males, their neuroendocrine effects and intracellular signaling patterns in females are not well determined.

Journal of Neurochemistry, 2003

Disturbed adaptations at the molecular and cellular levels following stress could represent compr... more Disturbed adaptations at the molecular and cellular levels following stress could represent compromised neural plasticity that contributes to the pathophysiology of stress-induced disorders. Evidence illustrates atrophy and cell death of stress-vulnerable neurones in the prefrontal cortex. Reduced plasticity may be realized through the destabilized function of selective proteins involved in organizing the neuronal skeleton and translating neurotrophic signals. To elucidate the mechanisms underlying these effects, rats were exposed to chronic footshock stress. Patterns of c-fos, phospho-extracellularregulated protein kinases 1/2 (ERK1/2), calcineurin and phospho-cyclic-AMP response-element binding protein (CREB) expression were subsequently investigated. The results indicate chronic stress-induced impairments in prefrontal and cingulate signal transduction cascades underlying neuronal plasticity. The medial prefrontal cortex, demonstrated functional hyperactivity and dendritic phospho-ERK1/2 hyperphosphorylation, while reduced c-fos and calcineurin immunoreactivity occurred in the cingulate cortex. Significantly reduced phospho-CREB expression in both cortical regions, considering its implication in brain-derived neurotrophic factor (BDNF) transcription, suggests reduced synaptic plasticity. This data confirms the damaging effect of stress on cortical activity, on a molecular level. Due to the association of these markers in the regulation of BDNF signalling, these findings suggest a central role for intracellular neurotrophin transduction members in the pathways underlying cellular actions of stress in the brain.

Experimental Brain Research, 2010

The immediate early gene Arc is emerging as a versatile, Wnely tuned system capable of coupling c... more The immediate early gene Arc is emerging as a versatile, Wnely tuned system capable of coupling changes in neuronal activity patterns to synaptic plasticity, thereby optimizing information storage in the nervous system. Here, we attempt to overview the Arc system spanning from transcriptional regulation of the Arc gene, to dendritic transport, metabolism, and translation of Arc mRNA, to post-translational modiWcation, localization, and degradation of Arc protein. Within this framework we discuss the function of Arc in regulation of actin cytoskeletal dynamics underlying consolidation of long-term potentiation (LTP) and regulation of AMPA-type glutamate receptor endocytosis underlying long-term depression (LTD) and homeostatic plasticity. Behaviorally, Arc has a key role in consolidation of explicit and implicit forms of memory, with recent work implicating Arc in adaptation to stress as well as maladaptive plasticity connected to drug addiction. Arc holds considerable promise as a "master regulator" of protein synthesis-dependent forms of synaptic plasticity, but the mechanisms that modulate and switch Arc function are only beginning to be elucidated.

European Journal of Neuroscience, 2002

Stress has been shown to affect brain structural plasticity, promote long-term changes in multipl... more Stress has been shown to affect brain structural plasticity, promote long-term changes in multiple neurotransmitter systems and cause neuronal atrophy. However, the mechanisms involved in these stress-related neural alterations are still poorly understood. Mitogen-activated protein kinase (MAPK) cascades play a crucial role in the transduction of neurotrophic signal from the cell surface to the nucleus and are implicated in the modulation of synaptic plasticity and neuronal survival. An intriguing possibility is that stress might in¯uence brain plasticity through its effects on selective members of such intracellular signalling cascades responsible for the transduction of neurotrophin signals. Here, we have investigated the effects of stress on the expression of three members of the MAPK/extracellular-regulated kinase (ERK) pathway such as phospho-ERK1, phospho-ERK2 and phospho-cAMP/calcium-responsive element-binding protein (CREB) in the adult rat brain. Male rats were subjected to mild footshocks and the patterns of protein expression were analysed after 21 consecutive days of stress. We found that chronic stress induced a pronounced and persistent ERK1/2 hyperphosphorylation in dendrites of the higher prefrontocortical layers (II and III) and a reduction of phospho-CREB expression in several cortical and subcortical regions. We hypothesized that defects in ERK signalling regulation combined with a reduced phospho-CREB activity may be a crucial mechanism by which sustained stress may induce atrophy of selective subpopulations of vulnerable cortical neurons and/or distal dendrites. Thus, ERK-mediated cortical abnormalities may represent a speci®c path by which chronic stress affects the functioning of cortical structures and causes selective neural network defects.

European Journal of Neuroscience, 2006

The delayed therapeutic onset observed in response to chronic antidepressant drug treatment is li... more The delayed therapeutic onset observed in response to chronic antidepressant drug treatment is little understood. While current theories emphasize effects on gene transcription, possible effects of antidepressant drugs on translation control pathways have not been explored. We examined the effect of the selective serotonergic reuptake inhibitor fluoxetine on regulation of two major determinants of mRNA translation, eukaryotic initiation factor 4E (eIF4E) and eukaryotic elongation factor 2 (eEF2). Chronic fluoxetine treatment induced hyperphosphorylation of eEF2 (Thr56) in prefrontal cortex, hippocampus and dentate gyrus of rats. By contrast, phosphorylation of eIF4E (Ser209) was observed specifically in the dentate gyrus. Acute fluoxetine treatment had no effect on translational factor activity. These findings suggest that region-specific regulation of translation contributes to the delayed action of antidepressant drugs such as fluoxetine.

The monoamine hypothesis of depression was coined over 30 years ago [1, 2]. This hypothesis propo... more The monoamine hypothesis of depression was coined over 30 years ago [1, 2]. This hypothesis proposes that there is an underlying biological basis for depression, namely a deficiency of the monoamine neurotransmitters norepinephrine, serotonin, and/or ...

Physiology & Behavior, 2008

Social defeat, resulting from the fight for a territory is based on the resident-intruder paradig... more Social defeat, resulting from the fight for a territory is based on the resident-intruder paradigm. A male rat intruder is placed in the territory of an older, bigger and more aggressive male resident and is defeated. In the present study, a double exposure to social defeat increased sleep fragmentation due to an increased amount of waking and slow-wave-sleep-1 (SWS-1) episodes. Also, social defeat increased the amount of slow-wave-sleep-2 (SWS-2). In repeated exposures to an open field, socially defeated rats showed low central activity and persistent defecation indicating high emotionality. The strongest effects of social defeat on sleep and open field behaviour were seen sub-chronically after stress. Social defeat did not induce changes in rapid eye movement (REM) sleep (e.g. total amount, latency), sleep latency, sexual activity, body weight or adrenal weight. A negative correlation between habituation in open field central activity and total sleep fragmentation indicates a commonality of effects of social defeat on both behaviour and sleep.