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1.
Mol Psychiatry ; 23(4): 904-913, 2018 04.
Article in English | MEDLINE | ID: mdl-27956743

ABSTRACT

Genetic susceptibility and environmental factors (such as stress) can interact to affect the likelihood of developing a mood disorder. Stress-induced changes in the hippocampus have been implicated in mood disorders, and mutations in several genes have now been associated with increased risk, such as brain-derived neurotrophic factor (BDNF). The hippocampus has important anatomical subdivisions, and pyramidal neurons of the vulnerable CA3 region show significant remodeling after chronic stress, but the mechanisms underlying their unique plasticity remain unknown. This study characterizes stress-induced changes in the in vivo translating mRNA of this cell population using a CA3-specific enhanced green fluorescent protein (EGFP) reporter fused to the L10a large ribosomal subunit (EGFPL10a). RNA-sequencing after isolation of polysome-bound mRNAs allows for cell-type-specific, genome-wide characterization of translational changes after stress. The data demonstrate that acute and chronic stress produce unique translational profiles and that the stress history of the animal can alter future reactivity of CA3 neurons. CA3-specific EGFPL10a mice were then crossed to the stress-susceptible BDNF Val66Met mouse line to characterize how a known genetic susceptibility alters both baseline translational profiles and the reactivity of CA3 neurons to stress. Not only do Met allele carriers exhibit distinct levels of baseline translation in genes implicated in ion channel function and cytoskeletal regulation, but they also activate a stress response profile that is highly dissimilar from wild-type mice. Closer examination of genes implicated in the mechanisms of neuroplasticity, such as the NMDA and AMPA subunits and the BDNF pathway, reveal how wild-type mice upregulate many of these genes in response to stress, but Met allele carriers fail to do so. These profiles provide a roadmap of stress-induced changes in a genetically homogenous population of hippocampal neurons and illustrate the profound effects of gene-environment interactions on the translational profile of these cells.


Subject(s)
Brain-Derived Neurotrophic Factor/metabolism , Neuronal Plasticity/physiology , Pyramidal Cells/metabolism , Animals , Brain-Derived Neurotrophic Factor/genetics , CA3 Region, Hippocampal/metabolism , Hippocampus/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Neuronal Plasticity/genetics , Neurons/metabolism , Polymorphism, Single Nucleotide/genetics , Stress, Physiological/genetics , Stress, Physiological/physiology , Transcriptome/genetics
2.
Mol Psychiatry ; 22(2): 296-305, 2017 02.
Article in English | MEDLINE | ID: mdl-27021815

ABSTRACT

Alzheimer's disease (AD) and age-related cognitive decline represent a growing health burden and involve the hippocampus, a vulnerable brain region implicated in learning and memory. To understand the molecular effects of aging on the hippocampus, this study characterized the gene expression changes associated with aging in rodents using RNA-sequencing (RNA-seq). The glutamate modulator, riluzole, which was recently shown to improve memory performance in aged rats, prevented many of the hippocampal age-related gene expression changes. A comparison of the effects of riluzole in rats against human AD data sets revealed that many of the gene changes in AD are reversed by riluzole. Expression changes identified by RNA-Seq were validated by qRT-PCR open arrays. Riluzole is known to increase the glutamate transporter EAAT2's ability to scavenge excess glutamate, regulating synaptic transmission. RNA-seq and immunohistochemistry confirmed an increase in EAAT2 expression in hippocampus, identifying a possible mechanism underlying the improved memory function after riluzole treatment.


Subject(s)
Cognition/drug effects , Excitatory Amino Acid Transporter 2/drug effects , Riluzole/therapeutic use , Age Factors , Aging/genetics , Aging/metabolism , Alzheimer Disease/genetics , Alzheimer Disease/metabolism , Animals , Cognitive Aging/physiology , Disease Models, Animal , Glutamic Acid/metabolism , Hippocampus/metabolism , Male , Memory/drug effects , Neuroprotective Agents/pharmacology , Rats , Rats, Sprague-Dawley , Riluzole/metabolism , Synaptic Transmission/physiology , Transcriptome/genetics
3.
Transl Psychiatry ; 3: e323, 2013 Nov 05.
Article in English | MEDLINE | ID: mdl-24193728

ABSTRACT

Several psychiatric and neurological diseases are associated with altered hippocampal neurogenesis, suggesting differing neural stem cell (NSC) function may play a critical role in these diseases. To investigate the role of resident NSCs in a murine model of psychiatric disease, we sought to isolate and characterize NSCs from alpha-calcium-/calmodulin-dependent protein kinase II heterozygous knockout (CaMK2α-hKO) mice, a model of schizophrenia/bipolar disorder. These mice display altered neurogenesis, impaired neuronal development and are part of a larger family possessing phenotypic and behavioral correlates of schizophrenia/bipolar disorder and a shared pathology referred to as the immature dentate gyrus (iDG). The extent to which NSCs contribute to iDG pathophysiology remains unclear. To address this, we established heterogeneous cultures of NSCs isolated from the hippocampal neuropoietic niche. When induced to differentiate, CaMK2α-hKO-derived NSCs recapitulate organotypic hippocampal neurogenesis, but generate larger numbers of immature neurons than wild-type (WT) littermates. Furthermore, mutant neurons fail to assume mature phenotypes (including morphology and MAP2/calbindin expression) at the same rate observed in WT counterparts. The increased production of immature neurons which fail to mature indicates that this reductionist model retains key animal- and iDG-specific maturational deficits observed in animal models and human patients. This is doubly significant, as these stem cells lack several developmental inputs present in vivo. Interestingly, NSCs were isolated from animals prior to the emergence of overt iDG pathophysiology, suggesting mutant NSCs may possess lasting intrinsic alterations and that altered NSC function may contribute to iDG pathophysiology in adult animals.


Subject(s)
Bipolar Disorder/genetics , Calcium-Calmodulin-Dependent Protein Kinase Type 2/genetics , Dentate Gyrus/growth & development , Neural Stem Cells/cytology , Neurogenesis/genetics , Neurons/cytology , Schizophrenia/genetics , Animals , Cells, Cultured , Dentate Gyrus/metabolism , Disease Models, Animal , Hippocampus/growth & development , Hippocampus/metabolism , Mice , Mice, Knockout , Neural Stem Cells/metabolism , Neurogenesis/physiology , Neurons/metabolism , Phenotype
4.
Transl Psychiatry ; 2: e135, 2012 Jul 10.
Article in English | MEDLINE | ID: mdl-22781168

ABSTRACT

Hippocampus-associated cognitive impairments are a common, highly conserved symptom of both schizophrenia (SCZ) and bipolar disorder (BPD). Although the hippocampus is likely an impacted region in SCZ/BPD patients, the molecular and cellular underpinnings of these impairments are difficult to identify. An emerging class of mouse models for these psychiatric diseases display similar cognitive impairments to those observed in human patients. The hippocampi of these mice possess a conserved pathophysiological alteration; we term the 'immature dentate gyrus' (iDG), characterized by increased numbers of calretinin-positive immature neuronal progenitors, a dearth of calbindin-positive mature neurons and (often) constitutively increased neurogenesis. Although these models provide a link between cellular dysfunction and behavioral alteration, limited translational validity exists linking the iDG to human pathophysiology. In this study, we report the initial identification of an iDG-like phenotype in the hippocampi of human SCZ/BPD patients. These findings suggest a new motif for the etiology of these diseases and link an emerging class of mouse models to the human disease condition.


Subject(s)
Bipolar Disorder/genetics , Dentate Gyrus/growth & development , Nerve Tissue Proteins/genetics , S100 Calcium Binding Protein G/genetics , Schizophrenia/genetics , Adult , Analysis of Variance , Animals , Bipolar Disorder/physiopathology , Calbindin 2 , Calbindins , Dentate Gyrus/physiopathology , Disease Models, Animal , Female , Humans , Immunohistochemistry , Male , Mice , Mice, Inbred C57BL , Middle Aged , Nerve Tissue Proteins/metabolism , Phenotype , S100 Calcium Binding Protein G/metabolism , Schizophrenia/physiopathology
5.
Br J Psychiatry ; 189: 20-5, 2006 Jul.
Article in English | MEDLINE | ID: mdl-16816301

ABSTRACT

BACKGROUND: The impact of anxiety disorders has not been well delineated in prospective studies of bipolar disorder. AIMS: To examine the association between anxiety and course of bipolar disorder, as defined by mood episodes, quality of life and role functioning. METHOD: A thousand thousand out-patients with bipolar disorder were followed prospectively for 1 year. RESULTS: A current comorbid anxiety disorder (present in 31.9% of participants) was associated with fewer days well, a lower likelihood of timely recovery from depression, risk of earlier relapse, lower quality of life and diminished role function over I year of prospective study. The negative impact was greater with multiple anxiety disorders. CONCLUSIONS: Anxiety disorders, including those present during relative euthymia, predicted a poorer bipolar course. The detrimental effects of anxiety were not simply a feature of mood state. Treatment studies targeting anxiety disorders will help to clarify the nature of the impact of anxiety on bipolar course.


Subject(s)
Anxiety Disorders/psychology , Bipolar Disorder/psychology , Adolescent , Adult , Anxiety Disorders/rehabilitation , Bipolar Disorder/rehabilitation , Comorbidity , Epidemiologic Methods , Female , Humans , Male , Middle Aged , Prognosis , Psychiatric Status Rating Scales , Quality of Life , Recurrence , Substance-Related Disorders/psychology , United States
6.
J Perinatol ; 26(6): 371-4, 2006 Jun.
Article in English | MEDLINE | ID: mdl-16724078

ABSTRACT

Two surviving female infants, born from a triplet pregnancy at 30 weeks gestation, were noted to have severe osteopenia and multiple fractures diagnosed at 20 days of age. Their mother had been treated for preterm labor with intravenous magnesium sulfate from week 22 until their birth at 30 weeks gestation. At birth, the triplets exhibited craniotabes with enlarged fontanelles and sutures. All developed Respiratory Distress Syndrome (RDS) and the two surviving infants required prolonged respiratory support. Serum calcium and phosphate levels were normal and alkaline phosphatase levels were increased. The infants were treated with supplements of calcium and phosphorous, with resultant healing of the multiple fractures without deformity. Fetal magnesium toxicity impairs bone mineralization and can lead to serious bone demineralization that may cause fractures in the newborn period that complicate recovery from respiratory disease. Early recognition and treatment may minimize complications related to osteopenia caused by fetal magnesium toxicity.


Subject(s)
Bone Demineralization, Pathologic/chemically induced , Fetus/drug effects , Fractures, Bone/chemically induced , Magnesium/poisoning , Adult , Bone Demineralization, Pathologic/diagnostic imaging , Fatal Outcome , Female , Femur/diagnostic imaging , Fractures, Bone/diagnostic imaging , Humans , Infant, Newborn , Injections, Intravenous , Magnesium Sulfate/administration & dosage , Magnesium Sulfate/poisoning , Magnesium Sulfate/therapeutic use , Male , Obstetric Labor, Premature/drug therapy , Pregnancy , Radiography , Ribs/diagnostic imaging , Tibia/diagnostic imaging , Tocolytic Agents/administration & dosage , Tocolytic Agents/poisoning , Tocolytic Agents/therapeutic use , Triplets
8.
Behav Neurosci ; 114(5): 998-1004, 2000 Oct.
Article in English | MEDLINE | ID: mdl-11085615

ABSTRACT

Fear-potentiated startle was assessed in mice with a targeted disruption of the alpha and delta isoforms of the transcription factor cAMP response element binding protein (CREB) 24 hr after 5 tone + shock training trials. Whereas wild-type mice showed fear-potentiated startle that persisted up to 45 days after training, CREBalphadelta-/- mice failed to show fear-potentiated startle. However, CREBalphadelta-/- and wild-type mice had similar startle amplitudes and similar magnitudes of prepulse inhibition of startle, suggesting that CREBalphadelta-/- mice have no obvious sensory or motor deficits. These results add to the literature indicating that CREB-activated transcription plays a critical role in the formation of long-term memory and illustrate the utility of the fear-potentiated startle paradigm for assessing cognition in genetically altered mice.


Subject(s)
Fear , Reflex, Startle/physiology , Animals , Binding, Competitive/physiology , Cognition/physiology , Cyclic AMP/metabolism , Male , Mice , Mice, Mutant Strains , Transcription Factors/metabolism
9.
Acad Med ; 75(10): 1041, 2000 Oct.
Article in English | MEDLINE | ID: mdl-11031157

ABSTRACT

Feedback is an essential component of medical education and adult learning; however, there are several challenges inherent in measuring the feedback directed at medical students. The authors describe the use of a daily e-mail questionnaire to gather information from medical students about the feedback they receive.


Subject(s)
Education, Medical/methods , Feedback , United States
10.
J Anxiety Disord ; 14(2): 109-32, 2000.
Article in English | MEDLINE | ID: mdl-10864381

ABSTRACT

In 1994 there were 33.2 million older adults (65 years of age and older) in the United States, and approximately one quarter of these older adults meet diagnostic criteria for some mental disorder. Anxiety is among the most prevalent psychiatric disorder in older adults. However, insufficient research has been conducted on the assessment of anxiety in older adults. The purpose of this article was to provide an overview of issues to consider in assessing anxiety in older adults. First, a discussion of factors that may influence current prevalence and incidence figures is provided. Second, age-related differences in factors that can influence the experience and presentation of anxiety symptoms are considered. Third, age-related factors that can influence the assessment process or outcome are presented. Fourth, a discussion on the important role of multimethod assessment and the psychometric adequacy of available anxiety assessment instruments is presented. Finally, recommendations for clinical assessment and future research are provided.


Subject(s)
Anxiety Disorders/diagnosis , Aged , Anxiety Disorders/complications , Anxiety Disorders/epidemiology , Cognition Disorders/complications , Female , Humans , Male , Prevalence , Psychiatric Status Rating Scales , Surveys and Questionnaires
12.
Hippocampus ; 10(1): 47-56, 2000.
Article in English | MEDLINE | ID: mdl-10706216

ABSTRACT

The ability to learn and remember individuals is critical for the stability of social groups. Social recognition reflects the ability of mice to identify and remember conspecifics. Social recognition is assessed as a decrease in spontaneous investigation behaviors observed in a mouse reexposed to a familiar conspecific. Our results demonstrate that group-housed mice show social memory for a familiar juvenile when tested immediately, 30 min, 24 h, 3 days, and 7 days after a single 2-min-long interaction. Interestingly, chronic social isolation disrupts long-term, but not 30-min, social memory. Even a 24-h period of isolation disrupts long-term social memory, a result that may explain why previous investigators only observed short-term social memory in individually housed rodents. Although it has no obvious configural, relational, or spatial characteristics, here we show that social memory shares characteristics of other hippocampus-dependent memories. Ibotenic acid lesions of the hippocampus disrupt social recognition at 30 min, but not immediately after training. Furthermore, long-term, but not short-term social memory is dependent on protein synthesis and cyclic AMP responsive element binding protein (CREB) function. These results outline behavioral, systems, and molecular determinants of social recognition in mice, and they suggest that it is a powerful paradigm to investigate hippocampal learning and memory.


Subject(s)
Cyclic AMP Response Element-Binding Protein/genetics , Hippocampus/physiology , Memory/physiology , Social Behavior , Age Factors , Animals , Anisomycin/pharmacology , Behavior, Animal/drug effects , Behavior, Animal/physiology , Denervation , Hippocampus/surgery , Learning/drug effects , Learning/physiology , Male , Memory/drug effects , Mice , Mice, Inbred C57BL , Mice, Knockout , Protein Synthesis Inhibitors/pharmacology , Social Isolation
14.
Neurobiol Learn Mem ; 70(1-2): 44-61, 1998.
Article in English | MEDLINE | ID: mdl-9753586

ABSTRACT

Learning and remembering the location of food resources, predators, escape routes, and immediate kin is perhaps the most essential form of higher cognitive processing in mammals. Two of the most frequently studied forms of place learning are spatial learning and contextual conditioning. Spatial learning refers to an animal's capacity to learn the location of a reward, such as the escape platform in a water maze, while contextual conditioning taps into an animal's ability to associate specific places with aversive stimuli, such as an electric shock. Recently, transgenic and gene targeting techniques have been introduced to the study of place learning. In contrast with the abundant literature on the neuroanatomical substrates of place learning in rats, very little has been done in mice. Thus, in the first part of this article, we will review our studies on the involvement of the hippocampus in both spatial learning and contextual conditioning. Having demonstrated the importance of the hippocampus to place learning, we will then focus attention on the molecular and cellular substrates of place learning. We will show that just as in rats, mouse hippocampal pyramidal cells can show place specific firing. Then, we will review our evidence that hippocampal-dependent place learning involves a number of interacting physiological mechanisms with distinct functions. We will show that in addition to long-term potentiation, the hippocampus uses a number of other mechanisms, such as short-term-plasticity and changes in spiking, to process, store, and recall information. Much of the focus of this article is on genetic studies of learning and memory (L&M). However, there is no single experiment that can unambiguously connect any cellular or molecular mechanism with L&M. Instead, several different types of studies are required to determine whether any one mechanism is involved in L&M, including (i) the development of biologically based learning models that explain the involvement of a given mechanism in L&M, (ii) lesion experiments (genetics and pharmacology), (iii) direct observations during learning, and (iv) experiments where learning is triggered by turning on the candidate mechanism. We will show how genetic techniques will be key to unraveling the molecular and cellular basis of place learning.


Subject(s)
Brain Mapping , Hippocampus/physiology , Memory/physiology , Neuronal Plasticity/genetics , Animals , Avoidance Learning/physiology , Brain Mapping/methods , Discrimination Learning/physiology , Genetics, Behavioral , Learning/physiology , Long-Term Potentiation/genetics , Long-Term Potentiation/physiology , Memory/classification , Memory, Short-Term/physiology , Mice , Mice, Mutant Strains , Mice, Transgenic , Nerve Net , Point Mutation , Potassium/metabolism , Proteins/genetics , Rats , Species Specificity , Synapses
15.
J Acoust Soc Am ; 103(4): 2185-96, 1998 Apr.
Article in English | MEDLINE | ID: mdl-9566338

ABSTRACT

The performance of two techniques is compared for automated recognition of bird song units from continuous recordings. The advantages and limitations of dynamic time warping (DTW) and hidden Markov models (HMMs) are evaluated on a large database of male songs of zebra finches (Taeniopygia guttata) and indigo buntings (Passerina cyanea), which have different types of vocalizations and have been recorded under different laboratory conditions. Depending on the quality of recordings and complexity of song, the DTW-based technique gives excellent to satisfactory performance. Under challenging conditions such as noisy recordings or presence of confusing short-duration calls, good performance of the DTW-based technique requires careful selection of templates that may demand expert knowledge. Because HMMs are trained, equivalent or even better performance of HMMs can be achieved based only on segmentation and labeling of constituent vocalizations, albeit with many more training examples than DTW templates. One weakness in HMM performance is the misclassification of short-duration vocalizations or song units with more variable structure (e.g., some calls, and syllables of plastic songs). To address these and other limitations, new approaches for analyzing bird vocalizations are discussed.


Subject(s)
Auditory Perception/physiology , Automation/methods , Markov Chains , Vocalization, Animal/physiology , Animals , Birds , Learning , Male , Time Factors
16.
Annu Rev Neurosci ; 21: 127-48, 1998.
Article in English | MEDLINE | ID: mdl-9530494

ABSTRACT

The cAMP responsive element binding protein (CREB) is a nuclear protein that modulates the transcription of genes with cAMP responsive elements in their promoters. Increases in the concentration of either calcium or cAMP can trigger the phosphorylation and activation of CREB. This transcription factor is a component of intracellular signaling events that regulate a wide range of biological functions, from spermatogenesis to circadian rhythms and memory. Here we review the key features of CREB-dependent transcription, as well as the involvement of CREB in memory formation. Evidence from Aplysia, Drosophila, mice, and rats shows that CREB-dependent transcription is required for the cellular events underlying long-term but not short-term memory. While the work in Aplysia and Drosophila only involved CREB function in very simple forms of conditioning, genetic and pharmacological studies in mice and rats demonstrate that CREB is required for a variety of complex forms of memory, including spatial and social learning, thus indicating that CREB may be a universal modulator of processes required for memory formation.


Subject(s)
Cyclic AMP Response Element-Binding Protein/physiology , Memory/physiology , Animals
18.
J Appl Behav Anal ; 30(3): 411-22, 1997.
Article in English | MEDLINE | ID: mdl-9316256

ABSTRACT

The effects of reinforcement choice on task performance were examined with 6 individuals who had been diagnosed with severe to profound mental retardation. Five highly preferred items were identified for each participant via stimulus preference assessments. Participants then were exposed to choice and no-choice conditions that were alternated within reversal and multielement designs. During choice sessions, participants were permitted to select between two preferred stimuli contingent on responding. During no-choice sessions, the therapist delivered a single item contingent on responding. Preference for the stimuli was held constant across conditions by yoking the items delivered during no-choice sessions to those selected during the immediately preceding choice sessions. All participants exhibited similar rates of responding across choice and no-choice conditions. These findings indicate that for individuals with severe disabilities, access to choice may not improve task performance when highly preferred items are already incorporated into instructional programs.


Subject(s)
Behavior Therapy , Choice Behavior , Intellectual Disability/psychology , Motivation , Reinforcement, Psychology , Adolescent , Adult , Aggression/psychology , Child , Child, Preschool , Conditioning, Operant , Education of Intellectually Disabled , Female , Humans , Individuality , Intellectual Disability/rehabilitation , Male , Self-Injurious Behavior/prevention & control , Self-Injurious Behavior/psychology
19.
J Appl Behav Anal ; 30(3): 451-8, 1997.
Article in English | MEDLINE | ID: mdl-9316258

ABSTRACT

One method that has been demonstrated to improve the effectiveness of reinforcement is stimulus (reinforcer) variation (Egel, 1980). Egel found that bar pressing increased and responding occurred more rapidly during varied reinforcement than during constant reinforcement when identical stimuli were used across phases for 10 individuals with autism. The purpose of the current investigation was to assess the preferences of 7 individuals for varied presentation of slightly lower quality stimuli relative to constant access to the highest quality stimulus. Varied presentation was preferred over constant reinforcer presentation with 4 participants, and the opposite was true for 2 participants. One participant did not demonstrate a preference. These results suggest that stimulus variation may allow less preferred reinforcers to compete effectively with a more highly preferred reinforcer for some individuals.


Subject(s)
Autistic Disorder/psychology , Choice Behavior , Habituation, Psychophysiologic , Motivation , Reinforcement, Psychology , Adolescent , Attention , Autistic Disorder/therapy , Child , Decision Making , Female , Humans , Intellectual Disability/psychology , Intellectual Disability/therapy , Male , Rett Syndrome/psychology , Rett Syndrome/therapy , Token Economy
20.
Am J Addict ; 6(3): 224-31, 1997.
Article in English | MEDLINE | ID: mdl-9256988

ABSTRACT

The authors administered a five-item craving questionnaire daily to 86 outpatients to determine whether initial craving scores predicted the likelihood of initiation of abstinence within a 30-day period. Patients with higher mean craving scores during the first 3 days of the study were less likely to initiate abstinence. However the relationship between craving and abstinence initiation was not linear. Rather, patients in the top quartile of craving scores were significantly less likely to abstain than were patients in the lower three quartiles. The findings suggest that this rapid, easily administered craving questionnaire may have short-term predictive validity.


Subject(s)
Cocaine , Motivation , Substance-Related Disorders/psychology , Female , Humans , Male , Personality Assessment , Prognosis
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