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1.
Nat Commun ; 10(1): 2333, 2019 05 27.
Article in English | MEDLINE | ID: mdl-31133685

ABSTRACT

The tuning of neurons in area CA1 of the hippocampus emerges through a combination of non-spatial input from different sensory modalities and spatial information about the animal's position and heading direction relative to the spatial enclosure being navigated. The positional modulation of CA1 neuronal responses has been widely studied (e.g. place tuning), but less is known about the modulation of these neurons by heading direction. Here, utilizing electrophysiological recordings from CA1 pyramidal cells in freely moving mice, we report that a majority of neural responses are modulated by the heading-direction of the animal relative to a point within or outside their enclosure that we call a reference point. The finding of heading-direction modulation relative to reference points identifies a novel representation encoded in the neuronal responses of the dorsal hippocampus.


Subject(s)
CA1 Region, Hippocampal/physiology , Models, Neurological , Orientation/physiology , Place Cells/physiology , Animals , CA1 Region, Hippocampal/cytology , Electrodes, Implanted , Electrophysiological Phenomena , Male , Mice , Mice, Inbred C57BL , Models, Animal
2.
Genes Brain Behav ; 14(7): 503-15, 2015 Sep.
Article in English | MEDLINE | ID: mdl-26176662

ABSTRACT

Impairments in social behavior characterize many neurodevelopmental psychiatric disorders. In fact, the temporal emergence and trajectory of these deficits can define the disorder, specify their treatment and signal their prognosis. The sophistication of mouse models with neurobiological endophenotypes of many aspects of psychiatric diseases has increased in recent years, with the necessity to evaluate social behavior in these models. We adapted an assay for the multimodal characterization of social behavior at different development time points (juvenile, adolescent and adult) in control mice in different social contexts (specifically, different sex pairings). Although social context did not affect social behavior in juvenile mice, it did have an effect on the quantity and type of social interaction as well as ultrasonic vocalizations in both adolescence and adulthood. We compared social development in control mice to a transgenic mouse model of the increase in postsynaptic striatal D2R activity observed in patients with schizophrenia (D2R-OE mice). Genotypic differences in social interactions emerged in adolescence and appeared to become more pronounced in adulthood. That vocalizations emitted from dyads with a D2R-OE subject were negatively correlated with active social behavior while vocalizations from control dyads were positively correlated with both active and passive social behavior also suggest social deficits. These data show that striatal dopamine dysfunction plays an important role in the development of social behavior and mouse models such as the one studied here provide an opportunity for screening potential therapeutics at different developmental time points.


Subject(s)
Corpus Striatum/growth & development , Neurogenesis , Phenotype , Receptors, Dopamine D2/genetics , Social Behavior , Animals , Corpus Striatum/metabolism , Corpus Striatum/physiology , Female , Male , Mice , Mice, Inbred C57BL , Vocalization, Animal
3.
Proc Natl Acad Sci U S A ; 104(13): 5632-7, 2007 Mar 27.
Article in English | MEDLINE | ID: mdl-17369358

ABSTRACT

Working memory is a temporary memory store where information is held briefly until the appropriate behavior is produced. However, the improvement in the performance of working memory tasks with practice over days points to the existence of a long-lasting component associated with learning strategies that lead to optimal performance. Here we show that the improvement in the performance of mice in a radial maze working memory task required the integrity of the medial prefrontal cortex (mPFC). We further demonstrate that this improvement of working memory performance requires the synthesis of de novo proteins in the mPFC. We suggest that in addition to storing memory briefly the mPFC is also involved in the consolidation and storage of the long-term learning strategies used in working memory.


Subject(s)
Gene Expression Regulation , Learning , Memory, Short-Term , Prefrontal Cortex/metabolism , Animals , Anisomycin/pharmacology , Brain Mapping , Male , Maze Learning , Mice , Mice, Inbred C57BL , Prefrontal Cortex/physiology , Proteins/chemistry , Reversal Learning , Space Perception , Spatial Behavior
4.
Science ; 294(5544): 1030-8, 2001 Nov 02.
Article in English | MEDLINE | ID: mdl-11691980

ABSTRACT

One of the most remarkable aspects of an animal's behavior is the ability to modify that behavior by learning, an ability that reaches its highest form in human beings. For me, learning and memory have proven to be endlessly fascinating mental processes because they address one of the fundamental features of human activity: our ability to acquire new ideas from experience and to retain these ideas over time in memory. Moreover, unlike other mental processes such as thought, language, and consciousness, learning seemed from the outset to be readily accessible to cellular and molecular analysis. I, therefore, have been curious to know: What changes in the brain when we learn? And, once something is learned, how is that information retained in the brain? I have tried to address these questions through a reductionist approach that would allow me to investigate elementary forms of learning and memory at a cellular molecular level-as specific molecular activities within identified nerve cells.


Subject(s)
Gene Expression Regulation , Hippocampus/physiology , Memory/physiology , Neurons/physiology , Synapses/physiology , Animals , Aplysia/physiology , Learning/physiology , Long-Term Potentiation , Neural Pathways/physiology , Neurons, Afferent/physiology , Neurotransmitter Agents/metabolism , Second Messenger Systems/physiology , Signal Transduction , Synaptic Transmission , Transcription, Genetic
5.
Science ; 294(5546): 1547-50, 2001 Nov 16.
Article in English | MEDLINE | ID: mdl-11641465

ABSTRACT

A change in the efficiency of synaptic communication between neurons is thought to underlie learning. Consistent with recent studies of such changes, we find that long-lasting potentiation of synaptic transmission between cultured hippocampal neurons is accompanied by an increase in the number of clusters of postsynaptic glutamate receptors containing the subunit GluR1. In addition, potentiation is accompanied by a rapid and long-lasting increase in the number of clusters of the presynaptic protein synaptophysin and the number of sites at which synaptophysin and GluR1 are colocalized. These results suggest that potentiation involves rapid coordinate changes in the distribution of proteins in the presynaptic neuron as well as the postsynaptic neuron.


Subject(s)
Hippocampus/cytology , Long-Term Potentiation , Neurons/physiology , Receptors, AMPA/metabolism , Synapses/metabolism , Synaptic Transmission , Synaptophysin/metabolism , Actins/physiology , Animals , Anisomycin/pharmacology , Cells, Cultured , Cytochalasin D/pharmacology , Excitatory Postsynaptic Potentials , Glutamic Acid/metabolism , Glutamic Acid/pharmacology , Hippocampus/physiology , Immunohistochemistry , Nerve Tissue Proteins/metabolism , Neurons/metabolism , Protein Synthesis Inhibitors/pharmacology , Rats , Rats, Sprague-Dawley , Recombinant Fusion Proteins/metabolism , Synaptophysin/genetics , Transfection
6.
Neuron ; 32(1): 123-40, 2001 Oct 11.
Article in English | MEDLINE | ID: mdl-11604144

ABSTRACT

Long-lasting forms of synaptic plasticity like the late phase of LTP (L-LTP) typically require an elevation of cAMP, the recruitment of the cAMP-dependent protein kinase (PKA), and ultimately the activation of transcription and translation; some forms also require brain-derived neurotrophic factor (BDNF). Both cAMP and BDNF can activate mitogen-activated protein kinase (MAPK/ERK), which also plays a role in LTP. However, little is known about the mechanisms whereby cAMP, BDNF, and MAPK interact. We find that increases in cAMP can rapidly activate the BDNF receptor TrkB and induce BDNF-dependent long-lasting potentiation at the Schaffer collateral-CA1 synapse in hippocampus. Surprisingly, in these BDNF-dependent forms of potentiation, which are also MAPK dependent, TrkB activation is not critical for the activation of MAPK but instead appears to modulate the subcellular distribution and nuclear translocation of the activated MAPK.


Subject(s)
Brain-Derived Neurotrophic Factor/genetics , Brain-Derived Neurotrophic Factor/metabolism , Cyclic AMP/metabolism , Long-Term Potentiation/physiology , Mitogen-Activated Protein Kinases/metabolism , Active Transport, Cell Nucleus/physiology , Animals , Cell Nucleus/enzymology , Colforsin/pharmacology , Dendrites/chemistry , Dendrites/metabolism , Dendrites/ultrastructure , Excitatory Postsynaptic Potentials/drug effects , Excitatory Postsynaptic Potentials/physiology , Ligands , Membrane Potentials/drug effects , Membrane Potentials/physiology , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Knockout , Microscopy, Immunoelectron , Neuronal Plasticity/physiology , Phosphorylation , Presynaptic Terminals/chemistry , Presynaptic Terminals/metabolism , Presynaptic Terminals/ultrastructure , Receptor, trkB/analysis , Receptor, trkB/metabolism , Theta Rhythm
7.
Neuron ; 31(5): 713-26, 2001 Sep 13.
Article in English | MEDLINE | ID: mdl-11567612

ABSTRACT

We have developed a presenilin-1 (PS1) conditional knockout mouse (cKO), in which PS1 inactivation is restricted to the postnatal forebrain. The PS1 cKO mouse is viable and exhibits no gross abnormalities. The carboxy-terminal fragments of the amyloid precursor protein differentially accumulate in the cerebral cortex of cKO mice, while generation of beta-amyloid peptides is reduced. Expression of Notch downstream effector genes, Hes1, Hes5, and Dll1, is unaffected in the cKO cortex. Although basal synaptic transmission, long-term potentiation, and long-term depression at hippocampal area CA1 synapses are normal, the PS1 cKO mice exhibit subtle but significant deficits in long-term spatial memory. These results demonstrate that inactivation of PS1 function in the adult cerebral cortex leads to reduced Abeta generation and subtle cognitive deficits without affecting expression of Notch downstream genes.


Subject(s)
Alzheimer Disease/genetics , Amyloid beta-Peptides/biosynthesis , Amyloid beta-Protein Precursor/metabolism , Membrane Proteins/deficiency , Mice, Knockout/growth & development , Neuronal Plasticity/genetics , Synaptic Transmission/genetics , Alzheimer Disease/metabolism , Alzheimer Disease/physiopathology , Amyloid beta-Peptides/genetics , Amyloid beta-Protein Precursor/genetics , Animals , Axons/metabolism , Axons/ultrastructure , Cerebral Cortex/growth & development , Cerebral Cortex/metabolism , Cerebral Cortex/physiopathology , Disease Models, Animal , Gene Expression Regulation, Developmental/physiology , Genetic Vectors/physiology , Hippocampus/growth & development , Hippocampus/metabolism , Hippocampus/physiopathology , Maze Learning/physiology , Membrane Proteins/genetics , Membrane Proteins/metabolism , Memory Disorders/genetics , Memory Disorders/metabolism , Memory Disorders/physiopathology , Mice , Mice, Knockout/genetics , Mice, Knockout/metabolism , Neural Pathways/growth & development , Neural Pathways/metabolism , Neural Pathways/physiopathology , Presenilin-1 , Receptors, Notch , Signal Transduction/genetics , Space Perception/physiology
8.
J Neurosci ; 21(16): 6413-22, 2001 Aug 15.
Article in English | MEDLINE | ID: mdl-11487665

ABSTRACT

Plasticity at central synapses has long been thought to be the most likely mechanism for learning and memory, but testing that idea experimentally has proven to be difficult. For this reason, we have developed a simplified preparation of the Aplysia siphon withdrawal reflex that allows one to examine behavioral learning and memory while simultaneously monitoring synaptic connections between individual identified neurons in the CNS. We previously found that monosynaptic connections from LE siphon sensory neurons to LFS siphon motor neurons make a substantial contribution to the reflex in the siphon withdrawal preparation (Antonov et al., 1999a). We have now used that preparation to assess the contribution of various cellular mechanisms to classical conditioning of the reflex with a siphon tap conditioned stimulus (CS) and tail shock unconditioned stimulus (US). We find that, compared with unpaired training, paired training with the CS and US produces greater enhancement of siphon withdrawal and evoked firing of LFS neurons, greater facilitation of the complex PSP elicited in an LFS neuron by the siphon tap, and greater facilitation of the monosynaptic PSP elicited by stimulation of a single LE neuron. Moreover, the enhanced facilitation of monosynaptic LE-LFS PSPs is greater for LE neurons that fire during the siphon tap and correlates significantly with the enhancement of siphon withdrawal and evoked firing of the LFS neurons. These results provide the most direct evidence to date that activity-dependent plasticity at specific central synapses contributes to behavioral conditioning and support the idea that synaptic plasticity is a mechanism of learning and memory more generally.


Subject(s)
Association Learning/physiology , Conditioning, Classical/physiology , Neuronal Plasticity/physiology , Synaptic Transmission/physiology , Animals , Aplysia , Electroshock , Excitatory Postsynaptic Potentials/physiology , In Vitro Techniques , Motor Neurons/physiology , Neurons, Afferent/physiology , Physical Stimulation , Reflex/physiology , Synapses/physiology
10.
Cell ; 104(5): 675-86, 2001 Mar 09.
Article in English | MEDLINE | ID: mdl-11257222

ABSTRACT

The threshold for hippocampal-dependent synaptic plasticity and memory storage is thought to be determined by the balance between protein phosphorylation and dephosphorylation mediated by the kinase PKA and the phosphatase calcineurin. To establish whether endogenous calcineurin acts as an inhibitory constraint in this balance, we examined the effect of genetically inhibiting calcineurin on plasticity and memory. Using the doxycycline-dependent rtTA system to express a calcineurin inhibitor reversibly in the mouse brain, we find that the transient reduction of calcineurin activity facilitates LTP in vitro and in vivo. This facilitation is PKA dependent and persists over several days in vivo. It is accompanied by enhanced learning and strengthened short- and long-term memory in several hippocampal-dependent spatial and nonspatial tasks. The LTP and memory improvements are reversed fully by suppression of transgene expression. These results demonstrate that endogenous calcineurin constrains LTP and memory.


Subject(s)
Calcineurin/genetics , Conditioning, Psychological/physiology , Long-Term Potentiation/physiology , Memory, Short-Term/physiology , Animals , Anti-Bacterial Agents/pharmacology , Calcineurin Inhibitors , Dentate Gyrus/physiology , Doxycycline/pharmacology , Electric Stimulation , Form Perception/physiology , Gene Expression Regulation/drug effects , In Vitro Techniques , Mice , Mice, Inbred C57BL , Mice, Transgenic , Neuronal Plasticity/physiology , Signal Transduction/physiology , Transgenes/physiology
11.
JAMA ; 285(5): 594-600, 2001 Feb 07.
Article in English | MEDLINE | ID: mdl-11176865

ABSTRACT

Neurological and psychiatric illnesses are among the most common and most serious health problems in developed societies. The most promising advances in neurological and psychiatric diseases will require advances in neuroscience for their elucidation, prevention, and treatment. Technical advances have improved methods for identifying brain regions involved during various types of cognitive activity, for tracing connections between parts of the brain, for visualizing individual neurons in living brain preparations, for recording the activities of neurons, and for studying the activity of single-ion channels and the receptors for various neurotransmitters. The most significant advances in the past 20 years have come from the application to the nervous system of molecular genetics and molecular cell biology. Discovery of the monogenic disorder responsible for Huntington disease and understanding its pathogenesis can serve as a paradigm for unraveling the much more complex, polygenic disorders responsible for such psychiatric diseases as schizophrenia, manic depressive illness, and borderline personality disorder. Thus, a new degree of cooperation between neurology and psychiatry is likely to result, especially for the treatment of patients with illnesses such as autism, mental retardation, cognitive disorders associated with Alzheimer and Parkinson disease that overlap between the 2 disciplines.


Subject(s)
Mental Disorders , Nervous System Diseases , Neurology/trends , Neurosciences/trends , Psychology/trends , Research/trends , Animals , Humans
12.
Biosci Rep ; 21(5): 565-611, 2001 Oct.
Article in English | MEDLINE | ID: mdl-12168768

ABSTRACT

The biology of learning, and short-term and long-term memory, as revealed by Aplysia and other organisms, is reviewed.


Subject(s)
Genes/physiology , Learning/physiology , Memory/physiology , Synapses/physiology , Animals , Humans , Models, Biological
13.
Cell ; 103(4): 595-608, 2000 Nov 10.
Article in English | MEDLINE | ID: mdl-11106730

ABSTRACT

The memory for sensitization of the gill withdrawal reflex in Aplysia is reflected in facilitation of the monosynaptic connection between the sensory and motor neurons of the reflex. The switch from short- to long-term facilitation requires activation of CREB1, derepression of ApCREB2, and induction of ApC/EBP. In search for genes that act downstream from CREB1, we have identified a transcription activator, ApAF, which is stimulated by protein kinase A and can dimerize with both ApC/EBP and ApCREB2. ApAF is necessary for long-term facilitation induced by five pulses of serotonin, by activation of CREB1, or by derepression of ApCREB2. Overexpression of ApAF enhances the long-term facilitation further. Thus, ApAF is a candidate memory enhancer gene downstream from both CREB1 and ApCREB2.


Subject(s)
Long-Term Potentiation/physiology , Memory/physiology , Nerve Tissue Proteins , Repressor Proteins , Transcription Factors/metabolism , Amino Acid Sequence , Animals , Aplysia , Base Sequence , Cyclic AMP Response Element-Binding Protein , Cyclic AMP-Dependent Protein Kinases/metabolism , DNA-Binding Proteins/metabolism , Dimerization , Gene Library , Gills , Leucine Zippers , Models, Neurological , Molecular Sequence Data , Motor Neurons/physiology , Neurons, Afferent/physiology , Protein Binding , Reflex , Sequence Homology, Amino Acid , Transcription Factors/isolation & purification
14.
Curr Opin Neurobiol ; 10(5): 587-92, 2000 Oct.
Article in English | MEDLINE | ID: mdl-11084321

ABSTRACT

Long-lasting forms of learning-related synaptic plasticity require transcription and yet occur in a synapse-specific manner, indicating that there are mechanisms to target the products of gene expression to some but not other synapses of a given cell. Studies in a variety of systems have indicated that mRNA localization and synaptically regulated local protein synthesis constitute one such mechanism. The cellular and molecular mechanisms underlying RNA localization and regulated translation in neurons are just beginning to be delineated, and appear to be similar to those used in asymmetric non-neuronal cells.


Subject(s)
Nerve Tissue Proteins/biosynthesis , Neuronal Plasticity/physiology , Neurons/metabolism , Synapses/physiology , Animals , Humans , RNA, Messenger/biosynthesis
15.
Curr Opin Neurobiol ; 10(5): 612-24, 2000 Oct.
Article in English | MEDLINE | ID: mdl-11084324

ABSTRACT

The last decade of the 20th century has seen the development of cognitive neuroscience as an effort to understand how the brain represents mental events. We review the areas of emotional and motor memory, vision, and higher mental processes as examples of this new understanding. Progress in all of these areas has been swift and impressive, but much needs to be done to reveal the mechanisms of cognition at the local circuit and molecular levels. This work will require new methods for controlling gene expression in higher animals and in studying the interactions between neurons at multiple levels.


Subject(s)
Cognition/physiology , Cognitive Science/history , Memory/physiology , Vision, Ocular/physiology , Animals , History, 20th Century , Humans
16.
Proc Natl Acad Sci U S A ; 97(24): 13342-7, 2000 Nov 21.
Article in English | MEDLINE | ID: mdl-11087874

ABSTRACT

Hippocampal-based behavioral memories and hippocampal-based forms of synaptic plasticity, such as long-term potentiation, are divisible into short- and long-term phases, with the long-term phase requiring the synthesis of new proteins and mRNA for its persistence. By contrast, it is less clear whether long-term depression (LTD) can be divisible into phases. We here describe that in stable hippocampal organotypic cultures, LTD also is not a unitary event but a multiphase process. A prolonged stimulus of 900 stimuli spaced at 1 Hz for 15 min induces a late phase of LTD, which is protein- and mRNA synthesis-dependent. By contrast, a short train of the same 900 stimuli massed at 5 Hz for 3 min produces only a short-lasting LTD. This short-lasting LTD is capable of capturing late-phase LTD. The 5-Hz stimulus or the prolonged 1-Hz stimulus in the presence of protein synthesis inhibitors each can be transformed into an enduring late phase of depression when the prolonged stimulus is applied to another input in the same population of neurons.


Subject(s)
Excitatory Postsynaptic Potentials/physiology , Hippocampus/physiology , Nerve Tissue Proteins/genetics , Neuronal Plasticity/physiology , Pyramidal Cells/physiology , Synapses/physiology , Animals , Electric Stimulation , Nerve Tissue Proteins/biosynthesis , Organ Culture Techniques , RNA, Messenger/genetics , Rats , Rats, Sprague-Dawley
17.
Proc Natl Acad Sci U S A ; 97(21): 11581-6, 2000 Oct 10.
Article in English | MEDLINE | ID: mdl-11027355

ABSTRACT

Studies of sensitization and classical conditioning of the gill-withdrawal reflex in Aplysia have shown that the synaptic connections between identified glutamatergic sensory neurons and motor neurons can be enhanced in one of two ways: by a heterosynaptic (modulatory input-dependent) mechanism that gives rise with repetition to long-term facilitation and by a homosynaptic (activity-dependent) mechanism that gives rise with repetition to a facilitation that is partially blocked by 2-amino-5-phosphonovaleric acid and by injection of 1,2-bis(2-aminophenoxy)ethane-N,N,N', N'-tetraacetate (BAPTA) into the postsynaptic cell and is similar to long-term potentiation in the hippocampus. We here have examined how these two forms of facilitation interact at the level of an individual synaptic connection by using a culture preparation consisting of a single bifurcated sensory neuron that forms independent synaptic contacts with each of two spatially separated motor neurons. We find that the homosynaptic facilitation produced by a train of action potentials is cell wide and is evident at all of the terminals of the sensory neuron. By contrast, the heterosynaptic facilitation mediated by the modulatory transmitter serotonin (5-HT) can operate at the level of a single synapse. Homosynaptic activation gives rise to only a transient facilitation lasting a few hours, even when repeated in a spaced manner. The heterosynaptic facilitation produced by a single pulse of 5-HT, applied to one terminal of the sensory neuron, also lasts only minutes. However, when one or more homosynaptic trains of spike activity are paired with even a single pulse of 5-HT applied to one of the two branches of the sensory neuron, the combined actions lead to a selective enhancement in synaptic strength only at the 5-HT-treated branch that now lasts more than a day, and thus amplifies, by more than 20-fold, the duration of the individually produced homo- and heterosynaptic facilitation. This form of synapse-specific facilitation has unusual long-term properties. It does not require protein synthesis, nor is it accompanied by synaptic growth.


Subject(s)
Aplysia/physiology , Nerve Tissue Proteins/biosynthesis , Neuronal Plasticity , Serotonin/physiology , Synapses/physiology , Animals
18.
J Neurosci ; 20(21): 8096-102, 2000 Nov 01.
Article in English | MEDLINE | ID: mdl-11050131

ABSTRACT

To further elucidate the links among synaptic plasticity, hippocampal place cells, and spatial memory, place cells were recorded from wild-type mice and transgenic "R(AB)" mice with reduced forebrain protein kinase A (PKA) activity after introduction into a novel environment. Place cells in both strains were similar during the first exposure and were equally stable for recording sessions separated by 1 hr. Place cell stability in wild-type mice was unchanged for sessions separated by 24 hr but was reduced in R(AB) mice over the longer interval. This stability pattern parallels both the reduced late-phase long-term potentiation in hippocampal slices from R(AB) mice and the amnesia for context fear conditioning seen in R(AB) mice 24 but not 1 hr after training. The similar time courses of synaptic, network, and behavioral instability suggest that the genetic reduction of PKA activity is responsible for the defects at each level and support the idea that hippocampal synaptic plasticity is important in spatial memory.


Subject(s)
Cyclic AMP-Dependent Protein Kinases/metabolism , Hippocampus/physiology , Learning/physiology , Long-Term Potentiation/physiology , Pyramidal Cells/physiology , Space Perception/physiology , Action Potentials/physiology , Animals , Appetitive Behavior/physiology , Cyclic AMP-Dependent Protein Kinases/deficiency , Electrodes, Implanted , Hippocampus/cytology , Hippocampus/enzymology , Memory/physiology , Mice , Neuronal Plasticity/physiology , Pyramidal Cells/enzymology , Spatial Behavior/physiology
19.
J Neurosci ; 20(17): 6317-25, 2000 Sep 01.
Article in English | MEDLINE | ID: mdl-10964936

ABSTRACT

The lateral amygdala (LA) is thought to be critical for the specific acquisition of conditioned fear, and the emotionally charged memories related to fear are thought to require a form of synaptic plasticity related to long-term potentiation (LTP). Is LTP in the lateral amygdala enduring, and, if so, does it require gene expression and the synthesis of new protein? Using brain slices, we have examined the molecular-signaling pathway of LTP in the cortico-amygdala and the thalamo-amygdala pathways. We find that a single high-frequency train of stimuli induces a transient LTP (E-LTP); by contrast, five repeated high-frequency trains induce an enduring late phase of LTP (L-LTP), which is dependent on gene expression and on new protein synthesis. In both pathways the late phase of LTP is mediated by protein kinase A (PKA) and mitogen-activated protein kinase (MAPK). Application of the adenylyl cyclase activator forskolin induced L-LTP in both pathways, and this potentiation is blocked by inhibitors of protein synthesis. The late phase of LTP also is modulated importantly by beta-adrenergic agonists. An inhibitor of beta-adrenergic receptors blocks L-LTP; conversely, application of a beta-adrenergic agonist induces the L-LTP. Immunocytochemical studies show that both repeated tetanization and application of forskolin stimulate the phosphorylation of cAMP response element-binding proteins (CREB) in cells of the lateral nucleus of the amygdala. These results suggest that PKA and MAPK are critical for the expression of a persistent phase of LTP in the lateral amygdala and that this late component requires the synthesis of new protein and mRNA.


Subject(s)
Amygdala/physiology , Carbazoles , Cerebral Cortex/physiology , Cyclic AMP-Dependent Protein Kinases/metabolism , Long-Term Potentiation , Mitogen-Activated Protein Kinases/metabolism , Thalamus/physiology , Amygdala/enzymology , Animals , Auditory Cortex/physiology , Colforsin/pharmacology , Cyclic AMP Response Element-Binding Protein/metabolism , In Vitro Techniques , Indoles/pharmacology , Isoproterenol/pharmacology , Long-Term Potentiation/drug effects , Phosphorylation , Pyrroles/pharmacology , Rats , Rats, Sprague-Dawley , Receptors, Adrenergic, beta/drug effects , Receptors, Adrenergic, beta/physiology , Signal Transduction , Transcription, Genetic
20.
Annu Rev Neurosci ; 23: 343-91, 2000.
Article in English | MEDLINE | ID: mdl-10845068

ABSTRACT

One of the most significant developments in biology in the past half century was the emergence, in the late 1950s and early 1960s, of neuroscience as a distinct discipline. We review here factors that led to the convergence into a common discipline of the traditional fields of neurophysiology, neuroanatomy, neurochemistry, and behavior, and we emphasize the seminal roles played by David McKenzie Rioch, Francis O Schmitt, and especially Stephen W Kuffler in creating neuroscience as we now know it. The application of the techniques of molecular and cellular biology to the study of the nervous system has greatly accelerated our understanding of the mechanisms involved in neuronal signaling, neural development, and the function of the major sensory and motor systems of the brain. The elucidation of the underlying causes of most neurological and psychiatric disorders has proved to be more difficult; but striking progress is now being made in determining the genetic basis of such disorders as Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, and a number of ion channel and mitochondrial disorders, and a significant start has been made in identifying genetic factors in the etiology of such disorders as manic depressive illness and schizophrenia. These developments presage the emergence in the coming decades of a new nosology, certainly in neurology and perhaps also in psychiatry, based not on symptomatology but on the dysfunction of specific genes, molecules, neuronal organelles and particular neural systems.


Subject(s)
Neurology/trends , Neurosciences/trends , Psychiatry/trends , Animals , Humans , Memory , Mental Disorders/genetics , Nervous System Diseases/genetics , Neurodegenerative Diseases/genetics , Prefrontal Cortex/physiopathology , Schizophrenia/physiopathology , Schizophrenic Psychology
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