Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 19 de 19
Filter
Add more filters










Publication year range
1.
J Am Acad Dermatol ; 90(6): 1243-1245, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38296200
2.
iScience ; 26(4): 106240, 2023 Apr 21.
Article in English | MEDLINE | ID: mdl-37153443

ABSTRACT

Successfully navigating dynamic environments requires organisms to learn the consequences of their actions. The prelimbic prefrontal cortex (PL) formulates action-consequence memories and is modulated by addictive drugs like cocaine. We trained mice to obtain food rewards and then unexpectedly withheld reinforcement, triggering new action-consequence memory. New memory was disrupted by cocaine when delivered immediately following non-reinforcement, but not when delayed, suggesting that cocaine disrupted memory consolidation. Cocaine also rapidly inactivated cofilin, a primary regulator of the neuronal actin cytoskeleton. This observation led to the discovery that cocaine also within the time of memory consolidation elevated dendritic spine elimination and blunted spine formation rates on excitatory PL neurons, culminating in thin-type spine attrition. Training drug-naive mice to utilize inflexible response strategies also eliminated thin-type dendritic spines. Thus, cocaine may disrupt action-consequence memory, at least in part, by recapitulating neurobiological sequalae occurring in the formation of inflexible habits.

3.
JAMA Dermatol ; 158(7): 770-778, 2022 07 01.
Article in English | MEDLINE | ID: mdl-35612849

ABSTRACT

Importance: It has been suggested that Mohs surgery for skin cancer among individuals with limited life expectancy may be associated with needless risk and discomfort, along with increased health care costs. Objective: To investigate patient- and tumor-specific indications considered by clinicians for treatment of nonmelanoma skin cancer in older individuals. Design, Setting, and Participants: This multicenter, prospective cohort study was conducted using data from US private practice and academic centers. Included patients were those older than age 85 years presenting for skin cancer surgery and referred for Mohs surgery, with reference groups of those younger than age 85 years receiving Mohs surgery and those older than age 85 years not receiving Mohs surgery. Data were analyzed from November 2018 through January 2019. Exposures: Mohs surgery for nonmelanoma skin cancer. Main Outcomes and Measures: Reason for treatment selection. Results: Among 1181 patients older than age 85 years referred for Mohs surgery (724 [61.9%] men among 1169 patients with sex data; 681 individuals aged >85 to 88 years [57.9%] among 1176 patients with age data) treated at 22 sites, 1078 patients (91.3%) were treated by Mohs surgery, and 103 patients (8.7%) received alternate treatment. Patients receiving Mohs surgery were more likely to have tumors on the face (738 patients [68.5%] vs 26 patients [25.2%]; P < .001) and nearly 4-fold more likely to have high functional status (614 patients [57.0%] vs 16 patients [15.5%]; P < .001). Of 15 distinct reasons provided by surgeons for opting to proceed with Mohs surgery, the most common were patient desire for treatment with a high cure rate (712 patients [66.0%]), good or excellent patient functional status for age (614 patients [57.0%]), and high risk associated with the tumor based on histology (433 patients [40.2%]). Conclusions and Relevance: This study found that older patients who received Mohs surgery often had high functional status, high-risk tumors, and tumors located on the face. These findings suggest that timely surgical treatment may be appropriate in older patients given that their tumors may be aggressive, painful, disfiguring, and anxiety provoking.


Subject(s)
Carcinoma, Basal Cell , Skin Neoplasms , Aged , Carcinoma, Basal Cell/pathology , Carcinoma, Basal Cell/surgery , Female , Humans , Male , Mohs Surgery , Private Practice , Prospective Studies , Skin/pathology , Skin Neoplasms/pathology , Skin Neoplasms/surgery
4.
Commun Biol ; 5(1): 116, 2022 02 08.
Article in English | MEDLINE | ID: mdl-35136204

ABSTRACT

In day-to-day life, we often must choose between pursuing familiar behaviors or adjusting behaviors when new strategies might be more fruitful. The dorsomedial striatum (DMS) is indispensable for arbitrating between old and new action strategies. To uncover molecular mechanisms, we trained mice to generate nose poke responses for food, then uncoupled the predictive relationship between one action and its outcome. We then bred the mice that failed to rapidly modify responding. This breeding created offspring with the same tendencies, failing to inhibit behaviors that were not reinforced. These mice had less post-synaptic density protein 95 in the DMS. Also, densities of the melanocortin-4 receptor (MC4R), a high-affinity receptor for α-melanocyte-stimulating hormone, predicted individuals' response strategies. Specifically, high MC4R levels were associated with poor response inhibition. We next found that reducing Mc4r in the DMS in otherwise typical mice expedited response inhibition, allowing mice to modify behavior when rewards were unavailable or lost value. This process required inputs from the orbitofrontal cortex, a brain region canonically associated with response strategy switching. Thus, MC4R in the DMS appears to propel reward-seeking behavior, even when it is not fruitful, while moderating MC4R presence increases the capacity of mice to inhibit such behaviors.


Subject(s)
Plant Breeding , Receptor, Melanocortin, Type 4 , Animals , Corpus Striatum/metabolism , Mice , Receptor, Melanocortin, Type 4/genetics , Receptor, Melanocortin, Type 4/metabolism , Reward , alpha-MSH/metabolism
6.
J Comp Neurol ; 529(6): 1157-1183, 2021 04 15.
Article in English | MEDLINE | ID: mdl-32856297

ABSTRACT

The mesolimbic dopamine (DA) system is involved in the regulation of multiple behaviors, including feeding, and evidence demonstrates that the melanocortin system can act on the mesolimbic DA system to control feeding and other behaviors. The melanocortin-3 receptor (MC3R) is an important component of the melanocortin system, but its overall role is poorly understood. Because MC3Rs are highly expressed in the ventral tegmental area (VTA) and are likely to be the key interaction point between the melanocortin and mesolimbic DA systems, we set out to identify both the efferent projection patterns of VTA MC3R neurons and the location of the neurons providing afferent input to them. VTA MC3R neurons were broadly connected to neurons across the brain but were strongly connected to a discrete set of brain regions involved in the regulation of feeding, reward, and aversion. Surprisingly, experiments using monosynaptic rabies virus showed that proopiomelanocortin (POMC) and agouti-related protein (AgRP) neurons in the arcuate nucleus made few direct synapses onto VTA MC3R neurons or any of the other major neuronal subtypes in the VTA, despite being extensively labeled by general retrograde tracers injected into the VTA. These results greatly contribute to our understanding of the anatomical interactions between the melanocortin and mesolimbic systems and provide a foundation for future studies of VTA MC3R neurons and the circuits containing them in the control of feeding and other behaviors.


Subject(s)
Dopaminergic Neurons/metabolism , Neurons, Afferent/metabolism , Neurons, Efferent/metabolism , Receptor, Melanocortin, Type 3/biosynthesis , Ventral Tegmental Area/metabolism , Animals , Dopaminergic Neurons/chemistry , Female , Male , Mice , Mice, 129 Strain , Mice, Inbred C57BL , Mice, Transgenic , Neurons, Afferent/chemistry , Neurons, Efferent/chemistry , Receptor, Melanocortin, Type 3/analysis , Receptor, Melanocortin, Type 3/genetics , Ventral Tegmental Area/chemistry
7.
Obesity (Silver Spring) ; 27(11): 1874-1882, 2019 11.
Article in English | MEDLINE | ID: mdl-31562706

ABSTRACT

OBJECTIVE: Amphetamine was formerly used as a treatment to combat obesity, but amphetamine's use as an appetite suppressant was discontinued because of its significant abuse potential. Most of the rewarding and reinforcing effects of amphetamine differ by sex, with females showing higher levels of drug intake and amphetamine-induced motivation, relapse, and locomotion, but it is unknown whether amphetamine's effects on feeding also differ by sex. Furthermore, previous research on the anorectic effects of amphetamine has been focused primarily on its effects on baseline homeostatic feeding, but it is unknown whether amphetamine also affects hedonic, reward-related feeding, which is an important factor driving the rise in obesity levels. METHODS: This study tested whether amphetamine alters food intake in a sex-dependent manner in two reward-related feeding paradigms: a sucrose two-bottle choice test and a high-fat/high-sugar binge intake model. RESULTS: Amphetamine altered food intake equally in males and females in both paradigms, with higher doses significantly inhibiting feeding and low doses of amphetamine increasing feeding at later time points. CONCLUSIONS: Amphetamine's effects on feeding and drug reward may be mediated by distinct mechanisms, which could allow for the development of new approaches to combat obesity with limited abuse and addiction-related side effects.


Subject(s)
Amphetamine/pharmacology , Bulimia , Dietary Carbohydrates/administration & dosage , Dietary Fats/administration & dosage , Energy Intake/drug effects , Sucrose/administration & dosage , Animals , Appetite Depressants/pharmacology , Bulimia/chemically induced , Bulimia/metabolism , Bulimia/prevention & control , Dose-Response Relationship, Drug , Eating/drug effects , Female , Male , Mice , Mice, Inbred C57BL , Sex Factors
8.
J Neurosci ; 39(23): 4595-4605, 2019 06 05.
Article in English | MEDLINE | ID: mdl-30940719

ABSTRACT

An essential aspect of goal-directed decision-making is selecting actions based on anticipated consequences, a process that involves the orbitofrontal cortex (OFC) and potentially, the plasticity of dendritic spines in this region. To investigate this possibility, we trained male and female mice to nose poke for food reinforcers, or we delivered the same number of food reinforcers non-contingently to separate mice. We then decreased the likelihood of reinforcement for trained mice, requiring them to modify action-outcome expectations. In a separate experiment, we blocked action-outcome updating via chemogenetic inactivation of the OFC. In both cases, successfully selecting actions based on their likely consequences was associated with fewer immature, thin-shaped dendritic spines and a greater proportion of mature, mushroom-shaped spines in the ventrolateral OFC. This pattern was distinct from spine loss associated with aging, and we identified no effects on hippocampal CA1 neurons. Given that the OFC is involved in prospective calculations of likely outcomes, even when they are not observable, constraining spinogenesis while preserving mature spines may be important for solidifying durable expectations. To investigate causal relationships, we inhibited the RNA-binding protein fragile X mental retardation protein (encoded by Fmr1), which constrains dendritic spine turnover. Ventrolateral OFC-selective Fmr1 knockdown recapitulated the behavioral effects of inducible OFC inactivation (and lesions; also shown here), impairing action-outcome conditioning, and caused dendritic spine excess. Our findings suggest that a proper balance of dendritic spine plasticity within the OFC is necessary for one's ability to select actions based on anticipated consequences.SIGNIFICANCE STATEMENT Navigating a changing environment requires associating actions with their likely outcomes and updating these associations when they change. Dendritic spine plasticity is likely involved, yet relationships are unconfirmed. Using behavioral, chemogenetic, and viral-mediated gene silencing strategies and high-resolution microscopy, we find that modifying action-outcome expectations is associated with fewer immature spines and a greater proportion of mature spines in the ventrolateral orbitofrontal cortex (OFC). Given that the OFC is involved in prospectively calculating the likely outcomes of one's behavior, even when they are not observable, constraining spinogenesis while preserving mature spines may be important for maintaining durable expectations.


Subject(s)
Anticipation, Psychological/physiology , Dendritic Spines/physiology , Neuronal Plasticity/physiology , Prefrontal Cortex/physiology , Reward , Animals , Conditioning, Operant , Decision Making , Dendritic Spines/ultrastructure , Dependovirus/genetics , Feeding Behavior , Female , Fragile X Mental Retardation Protein/antagonists & inhibitors , Fragile X Mental Retardation Protein/genetics , Fragile X Mental Retardation Protein/physiology , Gene Knockdown Techniques , Genes, Reporter , Genetic Vectors/administration & dosage , Male , Mice , Mice, Inbred C57BL , Optogenetics , RNA Interference , RNA, Small Interfering/genetics , RNA, Small Interfering/pharmacology , Reinforcement, Psychology
10.
Nat Commun ; 8(1): 1861, 2017 11 30.
Article in English | MEDLINE | ID: mdl-29187752

ABSTRACT

The prelimbic prefrontal cortex is necessary for associating actions with their consequences, enabling goal-directed decision making. We find that the strength of action-outcome conditioning correlates with dendritic spine density in prelimbic cortex, suggesting that new action-outcome learning involves dendritic spine plasticity. To test this, we inhibited the cytoskeletal regulatory factor Rho kinase. We find that the inhibitor fasudil enhances action-outcome memory, resulting in goal-directed behavior in mice that would otherwise express stimulus-response habits. Fasudil transiently reduces prelimbic cortical dendritic spine densities during a period of presumed memory consolidation, but only when paired with new learning. Fasudil also blocks habitual responding for cocaine, an effect that persists over time, across multiple contexts, and depends on actin polymerization. We suggest that Rho kinase inhibition promotes goal-oriented action selection by augmenting the plasticity of prelimbic cortical dendritic spines during the formation of new action-outcome memories.


Subject(s)
1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine/analogs & derivatives , Cocaine/administration & dosage , Conditioning, Operant/drug effects , Decision Making/drug effects , Dopamine Uptake Inhibitors/administration & dosage , Drug-Seeking Behavior/drug effects , Protein Kinase Inhibitors/pharmacology , rho-Associated Kinases/antagonists & inhibitors , 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine/pharmacology , Animals , Dendritic Spines/drug effects , Dendritic Spines/pathology , Goals , Mice , Neuronal Plasticity/drug effects , Prefrontal Cortex/drug effects , Prefrontal Cortex/pathology , Reinforcement, Psychology , Self Administration
11.
Skinmed ; 14(2): 153-5, 2016.
Article in English | MEDLINE | ID: mdl-27319967

ABSTRACT

A 50-year-old woman presented to our clinic for evaluation of numerous recurrent, pruritic papules on her upper extremities. She reported a 2- to 3-year history of up to eight unique lesions on the bilateral upper arms that would initially appear as firm papules before gradually softening and flattening out, leaving residual pink macules (Figure 1A). Her medical history was notable for mild hyperlipidemia. On presentation, she had several erythematous papules with overlying telangiectasias scattered throughout her bilateral upper arms. One lesion of concern over the left deltoid had been present for 5 months without signs of regression (Figure 1B). Pathology of this and a similar lesion showed histiocytes forming Touton giant cells with foamy cytoplasm consistent with a xanthogranuloma (AXG). Results from immunoperoxidase stains were negative for factor XIIIa and CD1a, diffusely positive for CD68, and focally positive for S100 (Figure 2).


Subject(s)
Granuloma/pathology , Lupus Erythematosus, Systemic/pathology , Xanthomatosis/pathology , Female , Granuloma/complications , Humans , Hyperplasia/complications , Hyperplasia/pathology , Lupus Erythematosus, Systemic/complications , Middle Aged , Recurrence , Upper Extremity , Xanthomatosis/complications
12.
Eur J Neurosci ; 42(4): 2114-2121, 2015 Aug.
Article in English | MEDLINE | ID: mdl-26096050

ABSTRACT

The GABAA receptor mediates fast, inhibitory signaling, and cortical expression of the α1 subunit increases during postnatal development. Certain pathological stimuli such as stressors or prenatal cocaine exposure can interfere with this process, but causal relationships between GABAA α1 deficiency and complex behavioral outcomes remain unconfirmed. We chronically reduced GABAA α1 expression selectively in the medial prefrontal cortex (prelimbic subregion) of mice using viral-mediated gene silencing of Gabra1. Adolescent-onset Gabra1 knockdown delayed the acquisition of a cocaine-reinforced instrumental response but spared cocaine seeking in extinction and in a cue-induced reinstatement procedure. To determine whether response acquisition deficits could be associated with impairments in action-outcome associative learning and memory, we next assessed behavioral sensitivity to instrumental contingency degradation. In this case, the predictive relationship between familiar actions and their outcomes is violated. Adolescent-onset knockdown, although not adult-onset knockdown, delayed the expression of goal-directed response strategies in this task, resulting instead in inflexible habit-like modes of response. Thus, the maturation of medial prefrontal cortex GABAA α1 systems during adolescence appears necessary for goal-directed reward-related decision making in adulthood. These findings are discussed in the light of evidence that prolonged Gabra1 deficiency may impair synaptic plasticity.


Subject(s)
Conditioning, Operant/physiology , Decision Making/physiology , Receptors, GABA-A/metabolism , Reward , Age Factors , Animals , Cocaine/administration & dosage , Conditioning, Operant/drug effects , Dopamine Uptake Inhibitors/administration & dosage , Food , Green Fluorescent Proteins/genetics , Green Fluorescent Proteins/metabolism , HSP70 Heat-Shock Proteins/metabolism , Mice , Mice, Inbred C57BL , Mice, Transgenic , Prefrontal Cortex/metabolism , Receptors, GABA-A/genetics , Self Administration
13.
J Clin Invest ; 125(4): 1497-508, 2015 Apr.
Article in English | MEDLINE | ID: mdl-25751059

ABSTRACT

Synaptic plasticity is the ability of synapses to modulate the strength of neuronal connections; however, the molecular factors that regulate this feature are incompletely understood. Here, we demonstrated that mice lacking brain-specific angiogenesis inhibitor 1 (BAI1) have severe deficits in hippocampus-dependent spatial learning and memory that are accompanied by enhanced long-term potentiation (LTP), impaired long-term depression (LTD), and a thinning of the postsynaptic density (PSD) at hippocampal synapses. We showed that compared with WT animals, mice lacking Bai1 exhibit reduced protein levels of the canonical PSD component PSD-95 in the brain, which stems from protein destabilization. We determined that BAI1 prevents PSD-95 polyubiquitination and degradation through an interaction with murine double minute 2 (MDM2), the E3 ubiquitin ligase that regulates PSD-95 stability. Restoration of PSD-95 expression in hippocampal neurons in BAI1-deficient mice by viral gene therapy was sufficient to compensate for Bai1 loss and rescued deficits in synaptic plasticity. Together, our results reveal that interaction of BAI1 with MDM2 in the brain modulates PSD-95 levels and thereby regulates synaptic plasticity. Moreover, these results suggest that targeting this pathway has therapeutic potential for a variety of neurological disorders.


Subject(s)
Angiogenic Proteins/physiology , Guanylate Kinases/metabolism , Hippocampus/physiopathology , Learning Disabilities/genetics , Membrane Proteins/metabolism , Memory Disorders/genetics , Nerve Tissue Proteins/physiology , Neuronal Plasticity/physiology , Proto-Oncogene Proteins c-mdm2/physiology , Spatial Learning/physiology , Angiogenic Proteins/deficiency , Angiogenic Proteins/genetics , Animals , Brain/blood supply , Disks Large Homolog 4 Protein , Guanylate Kinases/deficiency , Guanylate Kinases/genetics , HEK293 Cells , Hippocampus/pathology , Humans , Learning Curve , Learning Disabilities/physiopathology , Long-Term Potentiation/physiology , Maze Learning/physiology , Membrane Proteins/deficiency , Membrane Proteins/genetics , Memory Disorders/physiopathology , Mice , Mice, Inbred C57BL , Mice, Knockout , Nerve Tissue Proteins/deficiency , Nerve Tissue Proteins/genetics , Neuronal Plasticity/genetics , Neurons/ultrastructure , Protein Interaction Mapping , Protein Processing, Post-Translational , Protein Structure, Tertiary , Recombinant Fusion Proteins/metabolism , Synaptic Transmission/physiology , Ubiquitination
14.
Neuropsychopharmacology ; 40(4): 1027-36, 2015 Mar.
Article in English | MEDLINE | ID: mdl-25348603

ABSTRACT

An essential aspect of goal-directed action selection is differentiating between behaviors that are more, or less, likely to be reinforced. Habits, by contrast, are stimulus-elicited behaviors insensitive to action-outcome contingencies and are considered an etiological factor in several neuropsychiatric disorders. Thus, isolating the neuroanatomy and neurobiology of goal-directed action selection on the one hand, and habit formation on the other, is critical. Using in vivo viral-mediated gene silencing, we knocked down Gabra1 in the orbitofrontal prefrontal cortex (oPFC) in mice, decreasing oPFC GABAAα1 expression, as well as expression of the synaptic marker PSD-95. Mice expressing Green Fluorescent Protein or Gabra1 knockdown in the adjacent M2 motor cortex served as comparison groups. Using instrumental response training followed by action-outcome contingency degradation, we then found that oPFC GABAAα1 deficiency impaired animals' ability to differentiate between actions that were more or less likely to be reinforced, though sensitivity to outcome devaluation and extinction were intact. Meanwhile, M2 GABAAα1 deficiency enhanced sensitivity to action-outcome relationships. Behavioral abnormalities following oPFC GABAAα1 knockdown were rescued by testing mice in a distinct context relative to that in which they had been initially trained. Together, our findings corroborate evidence that chronic GABAAα1 deficiency remodels cortical synapses and suggest that neuroplasticity within the healthy oPFC gates the influence of reward-related contextual stimuli. These stimuli might otherwise promote maladaptive habit-based behavioral response strategies that contribute to-or exacerbate-neuropsychiatric illness.


Subject(s)
Conditioning, Operant/physiology , Decision Making/physiology , Neuronal Plasticity/physiology , Prefrontal Cortex/physiology , Receptors, GABA-A/metabolism , Animals , Attention/physiology , Cognition Disorders/genetics , Disks Large Homolog 4 Protein , Extinction, Psychological/physiology , Green Fluorescent Proteins/genetics , Green Fluorescent Proteins/metabolism , Guanylate Kinases/metabolism , In Vitro Techniques , Integrases/genetics , Integrases/metabolism , Membrane Proteins/metabolism , Mice , Mice, Inbred C57BL , Mice, Transgenic , Prefrontal Cortex/cytology , Receptors, GABA-A/genetics , Reinforcement, Psychology , Synaptophysin/metabolism
15.
J Neurosci ; 33(7): 3107-12, 2013 Feb 13.
Article in English | MEDLINE | ID: mdl-23407965

ABSTRACT

Neurons in distinct brain regions remodel in response to postnatal stressor exposure, and structural plasticity may underlie stress-related modifications in behavioral outcomes. Given the persistence of stress-related diseases such as depression, a critical next step in identifying the contributions of neural structure to psychopathology will be to identify brain circuits and cell types that fail to recover from stressor exposure. We enumerated dendritic spines during and after chronic stress hormone exposure in hippocampal CA1, deep-layer prefrontal cortex, and the basal amygdala and also reconstructed dendritic arbors of CA1 pyramidal neurons. Corticosterone modified dendritic spine density in these regions, but with the exception of the orbitofrontal cortex, densities normalized with a recovery period. Dendritic retraction of hippocampal CA1 neurons and anhedonic-like insensitivity to a sucrose solution also persisted despite a recovery period. Using mice with reduced gene dosage of p190rhogap, a cytoskeletal regulatory protein localized to dendritic spines, we next isolated structural correlates of both behavioral vulnerability (spine elimination) and resilience (spine proliferation) to corticosterone within the orbital cortex. Our findings provide novel empirical support for the perspective that stress-related structural reorganization of certain neuron populations can persist despite a "recovery" period from stressor exposure and that these modifications may lay a structural foundation for stressor vulnerability-or resiliency-across the lifespan.


Subject(s)
Behavior, Animal/drug effects , Corticosterone/pharmacology , Neurons/drug effects , Resilience, Psychological/drug effects , Animals , CA1 Region, Hippocampal/cytology , CA1 Region, Hippocampal/drug effects , CA1 Region, Hippocampal/physiology , Dendritic Spines/drug effects , Dendritic Spines/physiology , Dendritic Spines/ultrastructure , GTPase-Activating Proteins/genetics , GTPase-Activating Proteins/physiology , Gene Dosage , Hippocampus/cytology , Hippocampus/drug effects , Lysine/analogs & derivatives , Male , Mice , Mice, Inbred C57BL , Stress, Psychological/pathology , rho GTP-Binding Proteins/physiology
16.
Commun Integr Biol ; 6(6): e26068, 2013 Nov 01.
Article in English | MEDLINE | ID: mdl-24563705

ABSTRACT

We recently reported that prolonged exposure to the glucocorticoid receptor (GR) ligand corticosterone impairs decision-making that is dependent on the predictive relationship between an action and its outcome (Gourley et al.; Proceedings of the National Academy of Sciences, 2012). Additionally, acute GR blockade, when paired with action-outcome conditioning, also blocks new learning. We then showed that dendritic spines in the prelimbic prefrontal cortex remodeled under both conditions. Nonetheless, the relationship between deep-layer dendritic spines and outcome-based decision-making remains opaque. We report here that a history of prolonged corticosterone exposure increases dendritic spine density in deep-layer prelimbic cortex. When spines are imaged simultaneously with corticosteroid exposure (i.e., without a washout period), dendritic spine densities are, however, reduced. Thus, the morphological response of deep-layer prelimbic cortical neurons to prolonged corticosteroid exposure may be quite dynamic, with spine elimination during a period of chronic exposure and spine proliferation during a subsequent washout period. We provide evidence, using a Rho-kinase inhibitor, that GR-mediated dendritic spine remodeling is causally related to complex decision-making. Finally, we conclude this report with evidence that a history of early-life (adolescent) GR blockade, unlike acute blockade in adulthood, enhances subsequent outcome-based decision-making. Together, our findings suggest that physiological levels of GR binding enable an organism to learn about the predictive relationship between an action and its outcome, but a history of GR blockade may, under some circumstances, also have beneficial consequences.

17.
Proc Natl Acad Sci U S A ; 109(50): 20714-9, 2012 Dec 11.
Article in English | MEDLINE | ID: mdl-23185000

ABSTRACT

Stressor exposure biases decision-making strategies from those based on the relationship between actions and their consequences to others restricted by stimulus-response associations. Chronic stressor exposure also desensitizes glucocorticoid receptors (GR) and diminishes motivation to acquire food reinforcement, although causal relationships are largely not established. We show that a history of chronic exposure to the GR ligand corticosterone or acute posttraining GR blockade with RU38486 makes rodents less able to perform actions based on their consequences. Thus, optimal GR binding is necessary for the consolidation of new response-outcome learning. In contrast, medial prefrontal (but not striatal) BDNF can account for stress-related amotivation, in that selective medial prefrontal cortical Bdnf knockdown decreases break-point ratios in a progressive-ratio task. Knockdown also increases vulnerability to RU38486. Despite the role of BDNF in dendritic spine reorganization, deep-layer spine remodeling does not obviously parallel progressive-ratio response patterns, but treatment with the Na(+)-channel inhibitor riluzole reverses corticosteroid-induced motivational deficits and restores prefrontal BDNF expression after corticosterone. We argue that when prefrontal neurotrophin systems are compromised, and GR-mediated hypothalamic-pituitary-adrenal axis feedback is desensitized (as in the case of chronic stress hormone exposure), amotivation and inflexible maladaptive response strategies that contribute to stress-related mood disorders result.


Subject(s)
Behavior, Animal/physiology , Brain-Derived Neurotrophic Factor/physiology , Prefrontal Cortex/physiology , Receptors, Glucocorticoid/physiology , Affect/drug effects , Affect/physiology , Amitriptyline/pharmacology , Animals , Antidepressive Agents, Tricyclic/pharmacology , Behavior, Animal/drug effects , Brain-Derived Neurotrophic Factor/antagonists & inhibitors , Brain-Derived Neurotrophic Factor/genetics , Conditioning, Psychological/drug effects , Conditioning, Psychological/physiology , Corticosterone/pharmacology , Corticosterone/physiology , Dendritic Spines/drug effects , Dendritic Spines/physiology , Gene Knockdown Techniques , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Mifepristone/pharmacology , Motivation/drug effects , Motivation/physiology , Prefrontal Cortex/drug effects , Rats , Rats, Sprague-Dawley , Receptors, Glucocorticoid/antagonists & inhibitors , Stress, Physiological
18.
J Neurosci ; 32(43): 15133-41, 2012 Oct 24.
Article in English | MEDLINE | ID: mdl-23100434

ABSTRACT

Directed transport of the mRNA binding protein, zipcode binding protein1 (ZBP1), into developing axons is believed to play an important role in mRNA localization and local protein synthesis. The role of molecular motors in this process is unclear. We elucidated a role for myosin Va (MyoVa) to modulate the axonal localization and transport of ZBP1 in axons. Using cultured rat hippocampal neurons, ZBP1 colocalized with MyoVa in axons and growth cones. Interaction of MyoVa with ZBP1 was evident by coimmunoprecipitation of endogenous and overexpressed proteins. Inhibition of MyoVa function with the globular tail domain (GTD) of MyoVa protein or short hairpin RNA led to an accumulation of ZBP1 in axons. Live cell imaging of mCherryZBP1 in neurons expressing GTD showed an increase in the number of motile particles, run length, and stimulated anterograde moving ZBP1 particles, suggesting that MyoVa controls availability of ZBP1 for microtubule-dependent transport. These findings suggest a novel regulatory role for MyoVa in the transport of ZBP1 within axons.


Subject(s)
Axons/metabolism , Myosin Heavy Chains/metabolism , Myosin Type V/metabolism , Neurons/cytology , Neurons/metabolism , RNA-Binding Proteins/metabolism , Animals , Cells, Cultured , Cerebral Cortex/cytology , Embryo, Mammalian , Female , Growth Cones/physiology , Hippocampus/cytology , Luminescent Proteins/genetics , Male , Myosin Heavy Chains/genetics , Myosin Type V/genetics , Nonlinear Dynamics , Protein Transport/genetics , RNA, Small Interfering/genetics , RNA, Small Interfering/metabolism , RNA-Binding Proteins/genetics , Rats , Time Factors , Transfection/methods
19.
J Immunol ; 176(11): 6681-9, 2006 Jun 01.
Article in English | MEDLINE | ID: mdl-16709827

ABSTRACT

Adhesion- and degranulation-promoting adapter protein (ADAP) is required in TCR-induced activation and proliferation of peripheral T cells. Loss of ADAP also impairs TCR-initiated inside-out activation of the integrin LFA-1 (CD11a/CD18, alphaLbeta2). In this study, we demonstrate that ADAP-deficient CD4/CD8 double-positive (DP) cells have a diminished ability to proliferate, and that these DP thymocytes up-regulate CD69 poorly in vivo. Moreover, in both MHC class I- and class II-restricted TCR transgenic models, loss of ADAP interferes with both positive and negative selection. ADAP deficiency also impairs the ability of transgene-bearing DP thymocytes to form conjugates with Ag-loaded presenting cells. These findings suggest that ADAP is critical for thymocyte development and selection.


Subject(s)
Adaptor Proteins, Signal Transducing/physiology , Cell Differentiation/immunology , Cell Proliferation , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism , Thymus Gland/immunology , Thymus Gland/metabolism , Adaptor Proteins, Signal Transducing/deficiency , Adaptor Proteins, Signal Transducing/genetics , Amino Acid Sequence , Animals , Antigen-Presenting Cells/immunology , Antigen-Presenting Cells/metabolism , CD4 Antigens/biosynthesis , CD8 Antigens/biosynthesis , Calcium/metabolism , Cell Adhesion/genetics , Cell Adhesion/immunology , Cell Degranulation/genetics , Cell Degranulation/immunology , Cell Differentiation/genetics , Cell Line, Tumor , Female , Lymphocyte Count , Male , Mice , Mice, Knockout , Mice, Transgenic , Molecular Sequence Data , T-Lymphocyte Subsets/cytology , Thymus Gland/cytology
SELECTION OF CITATIONS
SEARCH DETAIL
...