Alicia Brantley - Academia.edu (original) (raw)

Uploads

Papers by Alicia Brantley

Research paper thumbnail of Susceptibility and Resilience to Posttraumatic Stress Disorder-like Behaviors in Inbred Mice

Biological psychiatry, Jan 8, 2017

The limited neurobiological understanding of posttraumatic stress disorder (PTSD) has been partia... more The limited neurobiological understanding of posttraumatic stress disorder (PTSD) has been partially attributed to the need for improved animal models. Stress-enhanced fear learning (SEFL) in rodents recapitulates many PTSD-associated behaviors, including stress-susceptible and stress-resilient subgroups in outbred rats. Identification of subgroups requires additional behavioral phenotyping, a confound to mechanistic studies. We employed a SEFL paradigm in inbred male and female C57BL/6 mice that combines acute stress with fear conditioning to precipitate traumatic-like memories. Extinction and long-term retention of extinction were examined after SEFL. Further characterization of SEFL effects on male mice was performed with additional behavioral tests, determination of regional activation by Fos immunofluorescence, and RNA sequencing of the basolateral amygdala. Stressed animals displayed persistently elevated freezing during extinction. While more uniform in females, SEFL produced...

Research paper thumbnail of Corticotropin Releasing Factor Receptors and Agonistic Behavior in Syrian Hamsters

Research paper thumbnail of Melanocortin-3 receptors in the limbic system mediate feeding-related motivational responses during weight loss

Molecular Metabolism, 2016

Research paper thumbnail of Hippocampal Dopamine/DRD1 Signaling Dependent on the Ghrelin Receptor

Cell, 2015

Highlights d In hippocampal neurons GHSR1a and DRD1 forms heteromers in a complex with Ga q d DRD... more Highlights d In hippocampal neurons GHSR1a and DRD1 forms heteromers in a complex with Ga q d DRD1-induced hippocampal synaptic plasticity is dependent on GHSR1a and Ga q d DRD1 mediated learning and memory is dependent on Ga q-PLC rather than Ga s signaling d DRD1-induced hippocampal memory is regulated by allosteric DRD1:GHSR1a interactions

Research paper thumbnail of Deletion of ERK2 Mitogen-Activated Protein Kinase Identifies Its Key Roles in Cortical Neurogenesis and Cognitive Function

Journal of Neuroscience, 2008

The mitogen-activated protein (MAP) kinases ERK1 and ERK2 are critical intracellular signaling in... more The mitogen-activated protein (MAP) kinases ERK1 and ERK2 are critical intracellular signaling intermediates; however, little is known about their isoform-specific functions in vivo. We have examined the role of ERK2 in neural development by conditional inactivation of the murine mapk1/ERK2 gene in neural progenitor cells of the developing cortex. ERK MAP kinase (MAPK) activity in neural progenitor cells is required for neuronal cell fate determination. Loss of ERK2 resulted in a reduction in cortical thickness attributable to impaired proliferation of neural progenitors during the neurogenic period and the generation of fewer neurons. Mutant neural progenitor cells remained in an undifferentiated state until gliogenic stimuli induced their differentiation, resulting in the generation of more astrocytes. The mutant mice displayed profound deficits in associative learning. Importantly, we have identified patients with a 1 Mb microdeletion on chromosome 22q11.2 encompassing the MAPK1/ERK2 gene. These children, who have reduced ERK2 levels, exhibit microcephaly, impaired cognition, and developmental delay. These findings demonstrate an important role for ERK2 in cellular proliferation and differentiation during neural development as well as in cognition and memory formation.

Research paper thumbnail of Gonadal hormones modulate the display of submissive behavior in socially defeated female Syrian hamsters

Hormones and Behavior, 2005

Research paper thumbnail of Corticotropin Releasing Factor Receptors and Agonistic Behavior in Syrian Hamsters

The non-specific corticotropin releasing factor receptor (CRFR) agonist rat/human CRF has previou... more The non-specific corticotropin releasing factor receptor (CRFR) agonist rat/human CRF has previously been shown to enhance the expression of conditioned defeat (CD) in male Syrian hamsters. In addition, it has been shown that this agonist may increase the expression of aggressive behavior in previously undefeated hamsters, suggesting a general role for CRF in the expression of agonistic behavior. The current study further investigated the effects of CRF on agonistic behavior by examining which CRFR subtype is mediating these effects. In Experiment 1a, previously defeated and non-defeated hamsters received vehicle, ovine CRF (oCRF), a CRFR1-specific agonist, or human urocortin II (UCNII), a CRFR2-specific agonist, prior to testing with a non-aggressive intruder. oCRF significantly enhanced the expression of CD in defeated hamsters and showed a trend toward increased aggressive behavior in non-defeated hamsters, while UCNII had no effect. In Experiment 1b, previously defeated and non-...

Research paper thumbnail of Melanocortin-3 receptors in the limbic system mediate feeding-related motivational responses during weight loss

Molecular Metabolism, 2016

Appetitive responses to weight loss are mediated by a nutrient-sensing neural network comprised o... more Appetitive responses to weight loss are mediated by a nutrient-sensing neural network comprised of melanocortin neurons. The role of neural melanocortin-3 receptors (MC3R) in mediating these responses is enigmatic. Mc3r knockout mice exhibit a paradoxical phenotype of obesity and reduced feeding-related behaviors in situations of nutrient scarcity. Here we examined whether MC3Rs expressed in mesolimbic neurons regulate feeding-related motivational responses. Interactions between Mc3r genotype, cognitive function and energy balance on food self-administration were assessed using operant conditioning with fixed- and progressive ratio (FR1/PR1) settings. Inhibition of Mc3r transcription by a loxP-flanked transcriptional blocker (TB) in C57BL/6JN mice (Mc3r (TB/TB) ) was reversed in mesolimbic neurons using DAT-Cre (DAT-MC3R). Caloric restriction (CR) caused 10-15% weight loss and increased motivation to acquire food rewards during training sessions. c-Fos-expression in the nucleus accumbens was increased 1 h following food presentation. While exhibiting weight loss, total food self-administration, enhanced motivation to self-administer food rewards in training sessions held during CR and c-Fos-activation in the nucleus accumbens following re-feeding were all markedly attenuated in Mc3r (TB/TB) mice. In contrast, cognitive abilities were normal in Mc3r (TB/TB) mice. Total food self-administration during FR1 sessions was not rescued in DAT-MC3R mice, however enhanced motivational responses to self-administer food rewards in PR1 conditions were restored. The nutrient-partitioning phenotype observed with Mc3r-deficiency was not rescued in DAT-MC3R mice. Mesolimbic MC3Rs mediate enhanced motivational responses during CR. However, they are insufficient to restore normal caloric loading when food is presented during CR and do not affect metabolic conditions altering nutrient partitioning.

Research paper thumbnail of Neuronal death induced by misfolded prion protein is due to NAD+ depletion and can be relieved in vitro and in vivo by NAD+ replenishment

Brain : a journal of neurology, Jan 11, 2015

The mechanisms of neuronal death in protein misfolding neurodegenerative diseases such as Alzheim... more The mechanisms of neuronal death in protein misfolding neurodegenerative diseases such as Alzheimer's, Parkinson's and prion diseases are poorly understood. We used a highly toxic misfolded prion protein (TPrP) model to understand neurotoxicity induced by prion protein misfolding. We show that abnormal autophagy activation and neuronal demise is due to severe, neuron-specific, nicotinamide adenine dinucleotide (NAD(+)) depletion. Toxic prion protein-exposed neuronal cells exhibit dramatic reductions of intracellular NAD(+) followed by decreased ATP production, and are completely rescued by treatment with NAD(+) or its precursor nicotinamide because of restoration of physiological NAD(+) levels. Toxic prion protein-induced NAD(+) depletion results from PARP1-independent excessive protein ADP-ribosylations. In vivo, toxic prion protein-induced degeneration of hippocampal neurons is prevented dose-dependently by intracerebral injection of NAD(+). Intranasal NAD(+) treatment of ...

Research paper thumbnail of Growth hormone secretagogue receptor (GHS-R1a) knockout mice exhibit improved spatial memory and deficits in contextual memory

Behavioural Brain Research, 2012

Although the hormone ghrelin is best known for its stimulatory effect on appetite and regulation ... more Although the hormone ghrelin is best known for its stimulatory effect on appetite and regulation of growth hormone release, it is also reported to have beneficial effects on learning and memory formation in mice. Nevertheless, controversy exists about whether endogenous ghrelin acts on its receptors in extra-hypothalamic areas of the brain. The ghrelin receptor (GHS-R1a) is co-expressed in neurons that express dopamine receptor type-1 (DRD1a) and type-2 (DRD2), and we have shown that a subset of GHS-R1a, which are not occupied by the agonist (apo-GHSR1a), heterodimerize with these two receptors to regulate dopamine signaling in vitro and in vivo. To determine the consequences of ghsr ablation on brain function, congenic ghsr -/- mice on the C57BL6/J background were subjected to a battery of behavioral tests. We show that the ghsr -/- mice exhibit normal balance, movement, coordination, and pain sensation, outperform ghsr +/+ mice in the Morris water maze, but show deficits in contextual fear conditioning.

Research paper thumbnail of Hippocampal Dopamine/DRD1 Signaling Dependent on the Ghrelin Receptor

Cell, 2015

The ghrelin receptor (GHSR1a) and dopamine receptor-1 (DRD1) are coexpressed in hippocampal neuro... more The ghrelin receptor (GHSR1a) and dopamine receptor-1 (DRD1) are coexpressed in hippocampal neurons, yet ghrelin is undetectable in the hippocampus; therefore, we sought a function for apo-GHSR1a. Real-time single-molecule analysis on hippocampal neurons revealed dimerization between apo-GHSR1a and DRD1 that is enhanced by DRD1 agonism. In addition, proximity measurements support formation of preassembled apo-GHSR1a:DRD1:Gαq heteromeric complexes in hippocampal neurons. Activation by a DRD1 agonist produced non-canonical signal transduction via Gαq-PLC-IP3-Ca(2+) at the expense of canonical DRD1 Gαs cAMP signaling to result in CaMKII activation, glutamate receptor exocytosis, synaptic reorganization, and expression of early markers of hippocampal synaptic plasticity. Remarkably, this pathway is blocked by genetic or pharmacological inactivation of GHSR1a. In mice, GHSR1a inactivation inhibits DRD1-mediated hippocampal behavior and memory. Our findings identify a previously unrecognized mechanism essential for DRD1 initiation of hippocampal synaptic plasticity that is dependent on GHSR1a, and independent of cAMP signaling.

Research paper thumbnail of Susceptibility and Resilience to Posttraumatic Stress Disorder-like Behaviors in Inbred Mice

Biological psychiatry, Jan 8, 2017

The limited neurobiological understanding of posttraumatic stress disorder (PTSD) has been partia... more The limited neurobiological understanding of posttraumatic stress disorder (PTSD) has been partially attributed to the need for improved animal models. Stress-enhanced fear learning (SEFL) in rodents recapitulates many PTSD-associated behaviors, including stress-susceptible and stress-resilient subgroups in outbred rats. Identification of subgroups requires additional behavioral phenotyping, a confound to mechanistic studies. We employed a SEFL paradigm in inbred male and female C57BL/6 mice that combines acute stress with fear conditioning to precipitate traumatic-like memories. Extinction and long-term retention of extinction were examined after SEFL. Further characterization of SEFL effects on male mice was performed with additional behavioral tests, determination of regional activation by Fos immunofluorescence, and RNA sequencing of the basolateral amygdala. Stressed animals displayed persistently elevated freezing during extinction. While more uniform in females, SEFL produced...

Research paper thumbnail of Corticotropin Releasing Factor Receptors and Agonistic Behavior in Syrian Hamsters

Research paper thumbnail of Melanocortin-3 receptors in the limbic system mediate feeding-related motivational responses during weight loss

Molecular Metabolism, 2016

Research paper thumbnail of Hippocampal Dopamine/DRD1 Signaling Dependent on the Ghrelin Receptor

Cell, 2015

Highlights d In hippocampal neurons GHSR1a and DRD1 forms heteromers in a complex with Ga q d DRD... more Highlights d In hippocampal neurons GHSR1a and DRD1 forms heteromers in a complex with Ga q d DRD1-induced hippocampal synaptic plasticity is dependent on GHSR1a and Ga q d DRD1 mediated learning and memory is dependent on Ga q-PLC rather than Ga s signaling d DRD1-induced hippocampal memory is regulated by allosteric DRD1:GHSR1a interactions

Research paper thumbnail of Deletion of ERK2 Mitogen-Activated Protein Kinase Identifies Its Key Roles in Cortical Neurogenesis and Cognitive Function

Journal of Neuroscience, 2008

The mitogen-activated protein (MAP) kinases ERK1 and ERK2 are critical intracellular signaling in... more The mitogen-activated protein (MAP) kinases ERK1 and ERK2 are critical intracellular signaling intermediates; however, little is known about their isoform-specific functions in vivo. We have examined the role of ERK2 in neural development by conditional inactivation of the murine mapk1/ERK2 gene in neural progenitor cells of the developing cortex. ERK MAP kinase (MAPK) activity in neural progenitor cells is required for neuronal cell fate determination. Loss of ERK2 resulted in a reduction in cortical thickness attributable to impaired proliferation of neural progenitors during the neurogenic period and the generation of fewer neurons. Mutant neural progenitor cells remained in an undifferentiated state until gliogenic stimuli induced their differentiation, resulting in the generation of more astrocytes. The mutant mice displayed profound deficits in associative learning. Importantly, we have identified patients with a 1 Mb microdeletion on chromosome 22q11.2 encompassing the MAPK1/ERK2 gene. These children, who have reduced ERK2 levels, exhibit microcephaly, impaired cognition, and developmental delay. These findings demonstrate an important role for ERK2 in cellular proliferation and differentiation during neural development as well as in cognition and memory formation.

Research paper thumbnail of Gonadal hormones modulate the display of submissive behavior in socially defeated female Syrian hamsters

Hormones and Behavior, 2005

Research paper thumbnail of Corticotropin Releasing Factor Receptors and Agonistic Behavior in Syrian Hamsters

The non-specific corticotropin releasing factor receptor (CRFR) agonist rat/human CRF has previou... more The non-specific corticotropin releasing factor receptor (CRFR) agonist rat/human CRF has previously been shown to enhance the expression of conditioned defeat (CD) in male Syrian hamsters. In addition, it has been shown that this agonist may increase the expression of aggressive behavior in previously undefeated hamsters, suggesting a general role for CRF in the expression of agonistic behavior. The current study further investigated the effects of CRF on agonistic behavior by examining which CRFR subtype is mediating these effects. In Experiment 1a, previously defeated and non-defeated hamsters received vehicle, ovine CRF (oCRF), a CRFR1-specific agonist, or human urocortin II (UCNII), a CRFR2-specific agonist, prior to testing with a non-aggressive intruder. oCRF significantly enhanced the expression of CD in defeated hamsters and showed a trend toward increased aggressive behavior in non-defeated hamsters, while UCNII had no effect. In Experiment 1b, previously defeated and non-...

Research paper thumbnail of Melanocortin-3 receptors in the limbic system mediate feeding-related motivational responses during weight loss

Molecular Metabolism, 2016

Appetitive responses to weight loss are mediated by a nutrient-sensing neural network comprised o... more Appetitive responses to weight loss are mediated by a nutrient-sensing neural network comprised of melanocortin neurons. The role of neural melanocortin-3 receptors (MC3R) in mediating these responses is enigmatic. Mc3r knockout mice exhibit a paradoxical phenotype of obesity and reduced feeding-related behaviors in situations of nutrient scarcity. Here we examined whether MC3Rs expressed in mesolimbic neurons regulate feeding-related motivational responses. Interactions between Mc3r genotype, cognitive function and energy balance on food self-administration were assessed using operant conditioning with fixed- and progressive ratio (FR1/PR1) settings. Inhibition of Mc3r transcription by a loxP-flanked transcriptional blocker (TB) in C57BL/6JN mice (Mc3r (TB/TB) ) was reversed in mesolimbic neurons using DAT-Cre (DAT-MC3R). Caloric restriction (CR) caused 10-15% weight loss and increased motivation to acquire food rewards during training sessions. c-Fos-expression in the nucleus accumbens was increased 1 h following food presentation. While exhibiting weight loss, total food self-administration, enhanced motivation to self-administer food rewards in training sessions held during CR and c-Fos-activation in the nucleus accumbens following re-feeding were all markedly attenuated in Mc3r (TB/TB) mice. In contrast, cognitive abilities were normal in Mc3r (TB/TB) mice. Total food self-administration during FR1 sessions was not rescued in DAT-MC3R mice, however enhanced motivational responses to self-administer food rewards in PR1 conditions were restored. The nutrient-partitioning phenotype observed with Mc3r-deficiency was not rescued in DAT-MC3R mice. Mesolimbic MC3Rs mediate enhanced motivational responses during CR. However, they are insufficient to restore normal caloric loading when food is presented during CR and do not affect metabolic conditions altering nutrient partitioning.

Research paper thumbnail of Neuronal death induced by misfolded prion protein is due to NAD+ depletion and can be relieved in vitro and in vivo by NAD+ replenishment

Brain : a journal of neurology, Jan 11, 2015

The mechanisms of neuronal death in protein misfolding neurodegenerative diseases such as Alzheim... more The mechanisms of neuronal death in protein misfolding neurodegenerative diseases such as Alzheimer's, Parkinson's and prion diseases are poorly understood. We used a highly toxic misfolded prion protein (TPrP) model to understand neurotoxicity induced by prion protein misfolding. We show that abnormal autophagy activation and neuronal demise is due to severe, neuron-specific, nicotinamide adenine dinucleotide (NAD(+)) depletion. Toxic prion protein-exposed neuronal cells exhibit dramatic reductions of intracellular NAD(+) followed by decreased ATP production, and are completely rescued by treatment with NAD(+) or its precursor nicotinamide because of restoration of physiological NAD(+) levels. Toxic prion protein-induced NAD(+) depletion results from PARP1-independent excessive protein ADP-ribosylations. In vivo, toxic prion protein-induced degeneration of hippocampal neurons is prevented dose-dependently by intracerebral injection of NAD(+). Intranasal NAD(+) treatment of ...

Research paper thumbnail of Growth hormone secretagogue receptor (GHS-R1a) knockout mice exhibit improved spatial memory and deficits in contextual memory

Behavioural Brain Research, 2012

Although the hormone ghrelin is best known for its stimulatory effect on appetite and regulation ... more Although the hormone ghrelin is best known for its stimulatory effect on appetite and regulation of growth hormone release, it is also reported to have beneficial effects on learning and memory formation in mice. Nevertheless, controversy exists about whether endogenous ghrelin acts on its receptors in extra-hypothalamic areas of the brain. The ghrelin receptor (GHS-R1a) is co-expressed in neurons that express dopamine receptor type-1 (DRD1a) and type-2 (DRD2), and we have shown that a subset of GHS-R1a, which are not occupied by the agonist (apo-GHSR1a), heterodimerize with these two receptors to regulate dopamine signaling in vitro and in vivo. To determine the consequences of ghsr ablation on brain function, congenic ghsr -/- mice on the C57BL6/J background were subjected to a battery of behavioral tests. We show that the ghsr -/- mice exhibit normal balance, movement, coordination, and pain sensation, outperform ghsr +/+ mice in the Morris water maze, but show deficits in contextual fear conditioning.

Research paper thumbnail of Hippocampal Dopamine/DRD1 Signaling Dependent on the Ghrelin Receptor

Cell, 2015

The ghrelin receptor (GHSR1a) and dopamine receptor-1 (DRD1) are coexpressed in hippocampal neuro... more The ghrelin receptor (GHSR1a) and dopamine receptor-1 (DRD1) are coexpressed in hippocampal neurons, yet ghrelin is undetectable in the hippocampus; therefore, we sought a function for apo-GHSR1a. Real-time single-molecule analysis on hippocampal neurons revealed dimerization between apo-GHSR1a and DRD1 that is enhanced by DRD1 agonism. In addition, proximity measurements support formation of preassembled apo-GHSR1a:DRD1:Gαq heteromeric complexes in hippocampal neurons. Activation by a DRD1 agonist produced non-canonical signal transduction via Gαq-PLC-IP3-Ca(2+) at the expense of canonical DRD1 Gαs cAMP signaling to result in CaMKII activation, glutamate receptor exocytosis, synaptic reorganization, and expression of early markers of hippocampal synaptic plasticity. Remarkably, this pathway is blocked by genetic or pharmacological inactivation of GHSR1a. In mice, GHSR1a inactivation inhibits DRD1-mediated hippocampal behavior and memory. Our findings identify a previously unrecognized mechanism essential for DRD1 initiation of hippocampal synaptic plasticity that is dependent on GHSR1a, and independent of cAMP signaling.