Dopamine D2 receptors (D2Rs) in the nucleus accumbens (NAc) regulate motivated behavior, but the ... more Dopamine D2 receptors (D2Rs) in the nucleus accumbens (NAc) regulate motivated behavior, but the underlying neurobiological mechanisms remain unresolved. Here, we show that selective upregulation of D2Rs in the indirect pathway of the adult NAc enhances the willingness to work for food. Mechanistic studies in brain slices reveal that D2R upregulation attenuates inhibitory transmission at two main output projections of the indirect pathway, the classical long-range projections to the ventral pallidum (VP), as well as local collaterals to direct pathway medium spiny neurons. In vivo physiology confirms the reduction in indirect pathway inhibitory transmission to the VP, and inhibition of indirect pathway terminals to VP is sufficient to enhance motivation. In contrast, D2R upregulation in the indirect pathway does not disinhibit neuronal activity of the direct pathway in vivo. These data suggest that D2Rs in ventral striatal projection neurons promote motivation by weakening the canon...
Serotonin (5-HT) selective reuptake inhibitors (SSRIs) are widely used in the treatment of depres... more Serotonin (5-HT) selective reuptake inhibitors (SSRIs) are widely used in the treatment of depression and anxiety disorders, but responsiveness is uncertain and side effects often lead to discontinuation. Side effect profiles suggest that SSRIs reduce dopaminergic (DAergic) activity, but specific mechanistic insight is missing. Here we show in mice that SSRIs impair motor function by acting on 5-HT2C receptors in the substantia nigra pars reticulata (SNr), which in turn inhibits nigra pars compacta (SNc) DAergic neurons. SSRI-induced motor deficits can be reversed by systemic or SNr-localized 5-HT2C receptor antagonism. SSRIs induce SNr hyperactivity and SNc hypoactivity that can also be reversed by systemic 5-HT2C receptor antagonism. Optogenetic inhibition of SNc DAergic neurons mimics the motor deficits due to chronic SSRI treatment, whereas local SNr 5-HT2C receptor antagonism or optogenetic activation of SNc DAergic neurons reverse SSRI-induced motor deficits. Lastly, we find t...
BackgroundHypoxic-ischemic encephalopathy (HIE) is a major cause of neonatal morbidity and mortal... more BackgroundHypoxic-ischemic encephalopathy (HIE) is a major cause of neonatal morbidity and mortality. Therapeutic hypothermia (TH) is the only available intervention, but neuroprotection is incomplete and variable. Seizures are common in infants with HIE undergoing TH and may worsen outcome. Phenobarbital is sometimes added, although use of prophylactic phenobarbital is controversial in the neonate. We hypothesize that prophylactic phenobarbital (PB) will not reduce, and may enhance, the neuroprotective effects of TH on brain injury and motor outcomes in the postnatal-day 10 (P10) hypoxic-ischemic (HI) rat.MethodsP10 rat pups were subjected to unilateral HI and 4 h recovery with: normothermia (N); hypothermia (TH); hypothermia with phenobarbital (TH+PB). Brain damage was assessed longitudinally at 24 h and 2 weeks using brain MRI, and 12 weeks using histochemical analysis. Motor function was assessed with the beam walk and cylinder tests.ResultsTH and TH+PB induced neuroprotection, ...
Dopamine neurons in the ventral tegmental area use glutamate as a cotransmitter. To elucidate the... more Dopamine neurons in the ventral tegmental area use glutamate as a cotransmitter. To elucidate the behavioral role of the cotransmission, we targeted the glutamate-recycling enzyme glutaminase (gene Gls1). In mice with a dopamine transporter (Slc6a3)-driven conditional heterozygous (cHET) reduction of Gls1 in their dopamine neurons, dopamine neuron survival and transmission were unaffected, while glutamate cotransmission at phasic firing frequencies was reduced, enabling focusing the cotransmission. The mice showed normal emotional and motor behaviors, and an unaffected response to acute amphetamine. Strikingly, amphetamine sensitization was reduced and latent inhibition potentiated. These behavioral effects, also seen in global GLS1 HETs with a schizophrenia resilience phenotype, were not seen in mice with an Emx1-driven forebrain reduction affecting most brain glutamatergic neurons. Thus, a reduction in dopamine neuron glutamate cotransmission appears to mediate significant compone...
Proceedings of the National Academy of Sciences of the United States of America, May 15, 2017
Obsessive-compulsive disorder (OCD) is a chronic, disabling condition with inadequate treatment o... more Obsessive-compulsive disorder (OCD) is a chronic, disabling condition with inadequate treatment options that leave most patients with substantial residual symptoms. Structural, neurochemical, and behavioral findings point to a significant role for basal ganglia circuits and for the glutamate system in OCD. Genetic linkage and association studies in OCD point to SLC1A1, which encodes the neuronal glutamate/aspartate/cysteine transporter excitatory amino acid transporter 3 (EAAT3)/excitatory amino acid transporter 1 (EAAC1). However, no previous studies have investigated EAAT3 in basal ganglia circuits or in relation to OCD-related behavior. Here, we report a model of Slc1a1 loss based on an excisable STOP cassette that yields successful ablation of EAAT3 expression and function. Using amphetamine as a probe, we found that EAAT3 loss prevents expected increases in (i) locomotor activity, (ii) stereotypy, and (iii) immediate early gene induction in the dorsal striatum following ampheta...
The Journal of neuroscience : the official journal of the Society for Neuroscience, Jan 13, 2016
Connectivity between brain networks may adapt flexibly to cognitive demand, a process that could ... more Connectivity between brain networks may adapt flexibly to cognitive demand, a process that could underlie adaptive behaviors and cognitive deficits, such as those observed in neuropsychiatric conditions like schizophrenia. Dopamine signaling is critical for working memory but its influence on internetwork connectivity is relatively unknown. We addressed these questions in healthy humans using functional magnetic resonance imaging (during ann-back working-memory task) and positron emission tomography using the radiotracer [(11)C]FLB457 before and after amphetamine to measure the capacity for dopamine release in extrastriatal brain regions. Brain networks were defined by spatial independent component analysis (ICA) and working-memory-load-dependent connectivity between task-relevant pairs of networks was determined via a modified psychophysiological interaction analysis. For most pairs of task-relevant networks, connectivity significantly changed as a function of working-memory load. ...
In light of the clinical evidence implicating dopamine in schizophrenia and the prominent hypothe... more In light of the clinical evidence implicating dopamine in schizophrenia and the prominent hypotheses put forth regarding alterations in dopaminergic transmission in this disease, molecular imaging has been used to examine multiple aspects of the dopaminergic system. We review the imaging methods used and compare the findings across the different molecular targets. Findings have converged to suggest early dysregulation in the striatum, especially in the rostral caudate, manifesting as excess synthesis and release. Recent data showed deficit extending to most cortical regions and even to other extrastriatal subcortical regions not previously considered to be "hypodopaminergic" in schizophrenia. These findings yield a new topography for the dopaminergic dysregulation in schizophrenia. We discuss the dopaminergic innervation within the individual projection fields to provide a topographical map of this dual dysregulation and explore potential cellular and circuit-based mechanisms for brain region-dependent alterations in dopaminergic parameters. This refined knowledge is essential to better guide translational studies and efforts in early drug development.
Despite the well-established role of serotonin signaling in mood regulation, causal relationships... more Despite the well-established role of serotonin signaling in mood regulation, causal relationships between serotonergic neuronal activity and behavior remain poorly understood. Using a pharmacogenetic approach, we find that selectively increasing serotonergic neuronal activity in wild-type mice is anxiogenic and reduces floating in the forced-swim test, whereas inhibition has no effect on the same measures. In a developmental mouse model of altered emotional behavior, increased anxiety and depression-like behaviors correlate with reduced dorsal raphé and increased median raphé serotonergic activity. These mice display blunted responses to serotonergic stimulation and behavioral rescues through serotonergic inhibition. Furthermore, we identify opposing consequences of dorsal versus median raphé serotonergic neuron inhibition on floating behavior, together suggesting that median raphé hyperactivity increases anxiety, whereas a low dorsal/median raphé serotonergic activity ratio increases depression-like behavior. Thus, we find a critical role of serotonergic neuronal activity in emotional regulation and uncover opposing roles of median and dorsal raphé function.
The previous optimism about the efficacy of cholinomimetics for the treatment of age- and dementi... more The previous optimism about the efficacy of cholinomimetics for the treatment of age- and dementia-associated syndromes was based on the assumption that a neurotransmitter replacement strategy, similar to the successful treatment of the dopaminergic deficiency in Parkinson’s disease, would attenuate the behavioral consequences of loss of basal forebrain cholinergic neurons. This “cholinergic hypothesis’’ (e.g., Bartus et al., 1985) was derived mainly from correlative neuropathological evidence (Whitehouse et al., 1981; Bowen et al., 1976; Palmer et al., 1987; Procter et al., 1988), and from animal studies that used basal forebrain lesions as a neurological model or muscarinic blockade as a pharmacological model (Hagan and Morris, 1988) for the behavioral consequences of cholinergic cell loss (Smith, 1988). However, it has more recently become evident that: (1) in the absence of a specific cholinotoxin, the basal forebrain model is invalid in terms of revealing the consequences of disruption to the basal forebrain cholinergic system (Robbins et al., 1989a; Salter and Dudchenko, 1991); (2) muscarinic antagonism produces behavioral deficits that model only some of the symptoms of dementia but spare major aspects such as the failure to retrieve information from remote memory (e.g., Beatty et al., 1986); and (3) traditional cholinomimetic drugs do not appear to exhibit clinically useful effects (for review see Sarter et al., 1991a). Reviewing this literature, Fibiger (1991) concluded that the contribution of the cholinergic system to the cognitive decline in dementia is unsettled, and that “programs aimed at developing cholinergic pharmacotherapies for the cognitive deficits in AD are based more on faith than on established facts” (p. 223). Fibiger, as well as others (e.g., Whalley, 1989) predicts that successful therapies will become obvious only after we learn more about etiological processes.
Anhedonia is associated with poor social function in schizophrenia. Here, we examined this associ... more Anhedonia is associated with poor social function in schizophrenia. Here, we examined this association in individuals at clinical high risk (CHR) for schizophrenia and related psychotic disorders, taking into account social anxiety. We then explored correlations between anhedonia and basal metabolic activity in selected forebrain regions implicated in reward processing. In 62 CHR individuals and 37 healthy controls, we measured social adjustment (Social Adjustment Self-Report Scale), social and physical anhedonia (Chapman Revised Anhedonia Scales), and social anxiety (Social Anxiety Scale for Adolescents) in cross-section. In a subgroup of 25 CHR individuals for whom high-spatial-resolution basal-state functional magnetic resonance imaging data were available, we also assessed correlations of these socio-affective constructs with basal cerebral blood volume in orbitofrontal cortex and related regions involved in reward processing. Relative to controls, CHR individuals reported social impairment, greater social and physical anhedonia, and more social anxiety, exhibiting impairments comparable to schizophrenia. Regression analyses showed that anhedonia predicted social impairment and correlated negatively with basal cerebral blood volume within the orbitofrontal cortex (all P's<0.05). Anhedonia and social anxiety are prominent in CHR individuals. Trait-like anhedonia may be a core phenotype related to orbitofrontal cortical function that, independent of symptoms, predicts social impairment. These data provide a rationale for interventions that target anhedonia and related activity in orbitofrontal cortical circuits in CHR individuals.
Dopamine D2 receptors (D2Rs) in the nucleus accumbens (NAc) regulate motivated behavior, but the ... more Dopamine D2 receptors (D2Rs) in the nucleus accumbens (NAc) regulate motivated behavior, but the underlying neurobiological mechanisms remain unresolved. Here, we show that selective upregulation of D2Rs in the indirect pathway of the adult NAc enhances the willingness to work for food. Mechanistic studies in brain slices reveal that D2R upregulation attenuates inhibitory transmission at two main output projections of the indirect pathway, the classical long-range projections to the ventral pallidum (VP), as well as local collaterals to direct pathway medium spiny neurons. In vivo physiology confirms the reduction in indirect pathway inhibitory transmission to the VP, and inhibition of indirect pathway terminals to VP is sufficient to enhance motivation. In contrast, D2R upregulation in the indirect pathway does not disinhibit neuronal activity of the direct pathway in vivo. These data suggest that D2Rs in ventral striatal projection neurons promote motivation by weakening the canon...
Serotonin (5-HT) selective reuptake inhibitors (SSRIs) are widely used in the treatment of depres... more Serotonin (5-HT) selective reuptake inhibitors (SSRIs) are widely used in the treatment of depression and anxiety disorders, but responsiveness is uncertain and side effects often lead to discontinuation. Side effect profiles suggest that SSRIs reduce dopaminergic (DAergic) activity, but specific mechanistic insight is missing. Here we show in mice that SSRIs impair motor function by acting on 5-HT2C receptors in the substantia nigra pars reticulata (SNr), which in turn inhibits nigra pars compacta (SNc) DAergic neurons. SSRI-induced motor deficits can be reversed by systemic or SNr-localized 5-HT2C receptor antagonism. SSRIs induce SNr hyperactivity and SNc hypoactivity that can also be reversed by systemic 5-HT2C receptor antagonism. Optogenetic inhibition of SNc DAergic neurons mimics the motor deficits due to chronic SSRI treatment, whereas local SNr 5-HT2C receptor antagonism or optogenetic activation of SNc DAergic neurons reverse SSRI-induced motor deficits. Lastly, we find t...
BackgroundHypoxic-ischemic encephalopathy (HIE) is a major cause of neonatal morbidity and mortal... more BackgroundHypoxic-ischemic encephalopathy (HIE) is a major cause of neonatal morbidity and mortality. Therapeutic hypothermia (TH) is the only available intervention, but neuroprotection is incomplete and variable. Seizures are common in infants with HIE undergoing TH and may worsen outcome. Phenobarbital is sometimes added, although use of prophylactic phenobarbital is controversial in the neonate. We hypothesize that prophylactic phenobarbital (PB) will not reduce, and may enhance, the neuroprotective effects of TH on brain injury and motor outcomes in the postnatal-day 10 (P10) hypoxic-ischemic (HI) rat.MethodsP10 rat pups were subjected to unilateral HI and 4 h recovery with: normothermia (N); hypothermia (TH); hypothermia with phenobarbital (TH+PB). Brain damage was assessed longitudinally at 24 h and 2 weeks using brain MRI, and 12 weeks using histochemical analysis. Motor function was assessed with the beam walk and cylinder tests.ResultsTH and TH+PB induced neuroprotection, ...
Dopamine neurons in the ventral tegmental area use glutamate as a cotransmitter. To elucidate the... more Dopamine neurons in the ventral tegmental area use glutamate as a cotransmitter. To elucidate the behavioral role of the cotransmission, we targeted the glutamate-recycling enzyme glutaminase (gene Gls1). In mice with a dopamine transporter (Slc6a3)-driven conditional heterozygous (cHET) reduction of Gls1 in their dopamine neurons, dopamine neuron survival and transmission were unaffected, while glutamate cotransmission at phasic firing frequencies was reduced, enabling focusing the cotransmission. The mice showed normal emotional and motor behaviors, and an unaffected response to acute amphetamine. Strikingly, amphetamine sensitization was reduced and latent inhibition potentiated. These behavioral effects, also seen in global GLS1 HETs with a schizophrenia resilience phenotype, were not seen in mice with an Emx1-driven forebrain reduction affecting most brain glutamatergic neurons. Thus, a reduction in dopamine neuron glutamate cotransmission appears to mediate significant compone...
Proceedings of the National Academy of Sciences of the United States of America, May 15, 2017
Obsessive-compulsive disorder (OCD) is a chronic, disabling condition with inadequate treatment o... more Obsessive-compulsive disorder (OCD) is a chronic, disabling condition with inadequate treatment options that leave most patients with substantial residual symptoms. Structural, neurochemical, and behavioral findings point to a significant role for basal ganglia circuits and for the glutamate system in OCD. Genetic linkage and association studies in OCD point to SLC1A1, which encodes the neuronal glutamate/aspartate/cysteine transporter excitatory amino acid transporter 3 (EAAT3)/excitatory amino acid transporter 1 (EAAC1). However, no previous studies have investigated EAAT3 in basal ganglia circuits or in relation to OCD-related behavior. Here, we report a model of Slc1a1 loss based on an excisable STOP cassette that yields successful ablation of EAAT3 expression and function. Using amphetamine as a probe, we found that EAAT3 loss prevents expected increases in (i) locomotor activity, (ii) stereotypy, and (iii) immediate early gene induction in the dorsal striatum following ampheta...
The Journal of neuroscience : the official journal of the Society for Neuroscience, Jan 13, 2016
Connectivity between brain networks may adapt flexibly to cognitive demand, a process that could ... more Connectivity between brain networks may adapt flexibly to cognitive demand, a process that could underlie adaptive behaviors and cognitive deficits, such as those observed in neuropsychiatric conditions like schizophrenia. Dopamine signaling is critical for working memory but its influence on internetwork connectivity is relatively unknown. We addressed these questions in healthy humans using functional magnetic resonance imaging (during ann-back working-memory task) and positron emission tomography using the radiotracer [(11)C]FLB457 before and after amphetamine to measure the capacity for dopamine release in extrastriatal brain regions. Brain networks were defined by spatial independent component analysis (ICA) and working-memory-load-dependent connectivity between task-relevant pairs of networks was determined via a modified psychophysiological interaction analysis. For most pairs of task-relevant networks, connectivity significantly changed as a function of working-memory load. ...
In light of the clinical evidence implicating dopamine in schizophrenia and the prominent hypothe... more In light of the clinical evidence implicating dopamine in schizophrenia and the prominent hypotheses put forth regarding alterations in dopaminergic transmission in this disease, molecular imaging has been used to examine multiple aspects of the dopaminergic system. We review the imaging methods used and compare the findings across the different molecular targets. Findings have converged to suggest early dysregulation in the striatum, especially in the rostral caudate, manifesting as excess synthesis and release. Recent data showed deficit extending to most cortical regions and even to other extrastriatal subcortical regions not previously considered to be "hypodopaminergic" in schizophrenia. These findings yield a new topography for the dopaminergic dysregulation in schizophrenia. We discuss the dopaminergic innervation within the individual projection fields to provide a topographical map of this dual dysregulation and explore potential cellular and circuit-based mechanisms for brain region-dependent alterations in dopaminergic parameters. This refined knowledge is essential to better guide translational studies and efforts in early drug development.
Despite the well-established role of serotonin signaling in mood regulation, causal relationships... more Despite the well-established role of serotonin signaling in mood regulation, causal relationships between serotonergic neuronal activity and behavior remain poorly understood. Using a pharmacogenetic approach, we find that selectively increasing serotonergic neuronal activity in wild-type mice is anxiogenic and reduces floating in the forced-swim test, whereas inhibition has no effect on the same measures. In a developmental mouse model of altered emotional behavior, increased anxiety and depression-like behaviors correlate with reduced dorsal raphé and increased median raphé serotonergic activity. These mice display blunted responses to serotonergic stimulation and behavioral rescues through serotonergic inhibition. Furthermore, we identify opposing consequences of dorsal versus median raphé serotonergic neuron inhibition on floating behavior, together suggesting that median raphé hyperactivity increases anxiety, whereas a low dorsal/median raphé serotonergic activity ratio increases depression-like behavior. Thus, we find a critical role of serotonergic neuronal activity in emotional regulation and uncover opposing roles of median and dorsal raphé function.
The previous optimism about the efficacy of cholinomimetics for the treatment of age- and dementi... more The previous optimism about the efficacy of cholinomimetics for the treatment of age- and dementia-associated syndromes was based on the assumption that a neurotransmitter replacement strategy, similar to the successful treatment of the dopaminergic deficiency in Parkinson’s disease, would attenuate the behavioral consequences of loss of basal forebrain cholinergic neurons. This “cholinergic hypothesis’’ (e.g., Bartus et al., 1985) was derived mainly from correlative neuropathological evidence (Whitehouse et al., 1981; Bowen et al., 1976; Palmer et al., 1987; Procter et al., 1988), and from animal studies that used basal forebrain lesions as a neurological model or muscarinic blockade as a pharmacological model (Hagan and Morris, 1988) for the behavioral consequences of cholinergic cell loss (Smith, 1988). However, it has more recently become evident that: (1) in the absence of a specific cholinotoxin, the basal forebrain model is invalid in terms of revealing the consequences of disruption to the basal forebrain cholinergic system (Robbins et al., 1989a; Salter and Dudchenko, 1991); (2) muscarinic antagonism produces behavioral deficits that model only some of the symptoms of dementia but spare major aspects such as the failure to retrieve information from remote memory (e.g., Beatty et al., 1986); and (3) traditional cholinomimetic drugs do not appear to exhibit clinically useful effects (for review see Sarter et al., 1991a). Reviewing this literature, Fibiger (1991) concluded that the contribution of the cholinergic system to the cognitive decline in dementia is unsettled, and that “programs aimed at developing cholinergic pharmacotherapies for the cognitive deficits in AD are based more on faith than on established facts” (p. 223). Fibiger, as well as others (e.g., Whalley, 1989) predicts that successful therapies will become obvious only after we learn more about etiological processes.
Anhedonia is associated with poor social function in schizophrenia. Here, we examined this associ... more Anhedonia is associated with poor social function in schizophrenia. Here, we examined this association in individuals at clinical high risk (CHR) for schizophrenia and related psychotic disorders, taking into account social anxiety. We then explored correlations between anhedonia and basal metabolic activity in selected forebrain regions implicated in reward processing. In 62 CHR individuals and 37 healthy controls, we measured social adjustment (Social Adjustment Self-Report Scale), social and physical anhedonia (Chapman Revised Anhedonia Scales), and social anxiety (Social Anxiety Scale for Adolescents) in cross-section. In a subgroup of 25 CHR individuals for whom high-spatial-resolution basal-state functional magnetic resonance imaging data were available, we also assessed correlations of these socio-affective constructs with basal cerebral blood volume in orbitofrontal cortex and related regions involved in reward processing. Relative to controls, CHR individuals reported social impairment, greater social and physical anhedonia, and more social anxiety, exhibiting impairments comparable to schizophrenia. Regression analyses showed that anhedonia predicted social impairment and correlated negatively with basal cerebral blood volume within the orbitofrontal cortex (all P's<0.05). Anhedonia and social anxiety are prominent in CHR individuals. Trait-like anhedonia may be a core phenotype related to orbitofrontal cortical function that, independent of symptoms, predicts social impairment. These data provide a rationale for interventions that target anhedonia and related activity in orbitofrontal cortical circuits in CHR individuals.
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