Monoamine oxidase in neuropsychiatry and behavior.
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Animals↗
Biomedical subjects
R F Thompson
Publications and source records attributed to R F Thompson.
17beta-estradiol enhances NMDA receptor-mediated EPSPs and long-term potentiation.
Gonadal steroid hormones influence CNS functioning through a variety of different mechanisms. To test the hypothesis that estrogen modulates synaptic plasticity in the hippocampus, in vitro hippocampal slices from 2-mo-old Sprague-Dawley male rats were used to determine the effect of 17beta-estradiol on both N-methyl-D-aspartate (NMDA) receptor-mediated excitatory postsynaptic potentials (EPSPs) through intracellular recordings and long-term potentiation (LTP) through extracellular recordings. Intracellular EPSPs and extracellular field EPSPs (fEPSPs) were recorded from CA1 pyramidal cells by stimulating Schaffer collateral fibers. In intracellular experiments, slices were perfused with medium containing bicuculline (5 microM) and low Mg2+ (0.1 mM) to enhance the NMDA receptor-mediated currents and 6, 7-dinitroquinoxaline-2,3-dione (DNQX) (10 microM) to block the alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprianate (AMPA) receptor-mediated component. The effects of 17beta-estradiol on NMDA receptor-mediated activity were excitatory; concentrations >10 nM induced seizure activity, and lower concentrations (1 nM) markedly increased the amplitude of NMDA-mediated EPSPs (both the first and second responses increased during paired pulse stimulation by 180 and 197%, respectively). In extracellular experiments, slices perfused with 17beta-estradiol (100 pM) exhibited a pronounced, persisting, and significant enhancement of LTP of both the fEPSP slope (192%) and fEPSP amplitude (177%) compared with control slices (fEPSP slope = 155%; fEPSP amplitude = 156%) 30 min after high-frequency stimulation. These data demonstrate that estrogen enhances NMDA receptor-mediated currents and promotes an enhancement of LTP magnitude.
2-Amino-5-phosphonovalerate↗
Clinton Nathan Woolsey: November 30, 1904-January 14, 1993.
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Cerebral Cortex↗
Cerebellar brain-derived neurotrophic factor-TrkB defect associated with impairment of eyeblink conditioning in Stargazer mutant mice.
In the spontaneous ataxic mutant mouse stargazer, there is a selective reduction of brain-derived neurotrophic factor (BDNF) mRNA expression in the cerebellum. BDNF protein levels in the cerebellum are reduced by 70%. Despite normal levels of full-length and truncated TrkB receptor, constitutive and neurotrophin-4/5-induced tyrosine phosphorylation was significantly reduced in several signal transduction molecules, including phospholipase-Cgamma1, erk1, and erk2. Morphological examination revealed an increased number of external granule cells at postnatal day 15 and the presence of abnormal neurons resembling immature granule cells in the adult. These abnormalities are associated with a severe impairment in the acquisition of classical eyeblink conditioning, indicating cerebellar malfunction. Our data suggest that normal BDNF expression and TrkB signal transduction in the cerebellum are necessary for learning and plasticity in this model.
Animals↗
Selective changes in AMPA receptors in rabbit cerebellum following classical conditioning of the eyelid-nictitating membrane response.
alpha-Amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors are critically involved in several forms of synaptic plasticity proposed to be neural substrates for learning and memory, e.g., long-term potentiation and long-term depression (LTD). The present study was designed to determine changes in cerebellar AMPA receptors following classical conditioning of the eyeblink-nictitating membrane response (NMR) in the rabbit. Quantitative autoradiography was used to assess changes in ligand binding properties of cerebellar AMPA receptors following NMR conditioning elicited by pairing electrical stimulation of the pontine nuclei with an airpuff to the eye. [3H]AMPA and [3H]-6-cyano-7-nitroquinoxaline-2,3-dion (CNQX) binding were determined following preincubation of frozen-thawed brain tissue sections at 0 or 35 degreesC. With 0 degreesC preincubation, no significant differences in [3H]AMPA binding to cerebellar AMPA receptors were seen between any of the experimental groups tested. In contrast, preincubation at 35 degreesC revealed significant decreases in [3H]AMPA binding to the trained side of the cerebellar cortex resulting from paired presentations of the conditioned and the unconditioned stimuli, while unpaired presentations of the stimuli resulted in no significant effect. With 35 degreesC preincubation, there were no significant differences in [3H]CNQX binding between any of the experimental groups and no significant differences in [3H]AMPA binding in the untrained side of the cerebellum. These results indicate that NMR conditioning is associated with a selective modification of AMPA-receptor properties in brain structures involved in the storage of the associative memory. Furthermore, they support the hypothesis that cerebellar LTD, resulting from decreased synaptic efficacy at parallel fiber-Purkinje cell synapses mediated by a change in AMPA-receptor properties, is a form of synaptic plasticity that supports this type of learning.
6-Cyano-7-nitroquinoxaline-2,3-dione↗
AMPA receptor properties in adult rat hippocampus following environmental enrichment.
In adult rats, environmental enrichment has been shown to selectively increase -AMPA binding in the hippocampus but the molecular mechanisms underlying this effect remain unknown. We used in situ hybridization with antisense oligonucleotides to determine possible changes in the hippocampal expression of messenger RNAs for different subunits of AMPA receptors in adult rats following exposure to an enriched environment. Quantitative analysis revealed that mRNA levels for three subtypes of AMPA glutamate receptors (GluR1-3; Flip and Flop variants) were not modified in any hippocampal region after environmental enrichment. In addition, no differences were detected in the levels of GluR1 and GluR2/3 proteins in Western blots of hippocampal membranes from enriched rats. Nevertheless, quantitative ligand binding autoradiography indicated that environmental enrichment evoked a significant and uniform decrease in the capacity of calcium or phosphatidylserine (PS) to up-regulate -AMPA binding in various hippocampal regions but not in the cerebral cortex. These findings support previous observations suggesting that post-translational changes in AMPA receptor properties, as a result of the activation of calcium-dependent processes, may represent an important mechanism underlying long-term modifications of synaptic efficacy in the rat hippocampus.
Animals↗
Importance of the intracellular domain of NR2 subunits for NMDA receptor function in vivo.
NMDA receptors, a class of glutamate-gated cation channels with high Ca2+ conductance, mediate fast transmission and plasticity of central excitatory synapses. We show here that gene-targeted mice expressing NMDA receptors without the large intracellular C-terminal domain of any one of three NR2 subunits phenotypically resemble mice made deficient in that particular subunit. Mice expressing the NR2B subunit in a C-terminally truncated form (NR2B(deltaC/deltaC) mice) die perinatally. NR2A(deltaC/deltaC) mice are viable but exhibit impaired synaptic plasticity and contextual memory. These and NR2C(deltaC/deltaC) mice display deficits in motor coordination. C-terminal truncation of NR2 subunits does not interfere with the formation of gateable receptor channels that can be synaptically activated. Thus, the phenotypes of our mutants appear to reflect defective intracellular signaling.
Amino Acid Sequence↗
Inhibitory cerebello-olivary projections and blocking effect in classical conditioning.
The behavioral phenomenon of blocking indicates that the informational relationship between the conditioned stimulus and the unconditioned stimulus is essential in classical conditioning. The eyeblink conditioning paradigm is used to describe a neural mechanism that mediates blocking. Disrupting inhibition of the inferior olive, a structure that conveys unconditioned stimulus information (airpuff) to the cerebellum prevented blocking in rabbits. Recordings of cerebellar neuronal activity show that the inferior olive input to the cerebellum becomes suppressed as learning occurs. These results suggest that the inferior olive becomes functionally inhibited by the cerebellum during conditioning, and that this negative feedback process might be the neural mechanism mediating blocking.
Action Potentials↗
Exposure to a conditioned aversive environment interferes with long-term potentiation induction in the fimbria-CA3 pathway.
The effect of re-exposure of rats to an aversive environment on the induction of long-term potentiation was investigated in the CA3 region 3 and 12 h after contextual conditioning. Electro-physiological recordings showed that re-exposure of rats to the conditioning chamber produced a significant and long-lasting decrease in population spike amplitude at both post-conditioning delays. High-frequency stimulation of the fimbria induced a large and persistent increase in CA3 population spike amplitude (about 400% of baseline) in animals of control groups and shocked animals that were not re-exposed to the conditioning environment. However, high-frequency stimulation applied during re-exposure of shocked subjects 3 h after the initial exposure resulted in a small and transient increase in population spike amplitude (about 140% of baseline); when applied 12 h after the initial exposure, it produced a persistent depression of the response (-30% of baseline). Behavioural testing indicated that re-exposure of shocked animals to the conditioning environment elicited a qualitatively and quantitatively similar freezing behaviour at both post-conditioning delays (3 or 12 h). In contrast to the long-lasting decrease in CA3 population spike amplitude produced by re-exposure to the aversive environment, the level of freezing behaviour diminished rapidly within 10 min of exposure. These results suggest that, during exposure to a conditioned aversive environment, alterations in fimbria-CA3 neural processing may be dissociated from contextual fear-induced freezing behaviour. In addition, processes underlying long-term potentiation induction in fimbria-CA3 pathway may be opposite to those taking place during hippocampal processing of conditioned aversive contexts.
Animals↗
Evidence of plasticity in the pontocerebellar conditioned stimulus pathway during classical conditioning of the eyeblink response in the rabbit.
Electrical stimulation thresholds required to elicit eyeblinks with either pontine or cerebellar interpositus stimulation were measured before and after classical eyeblink conditioning with paired pontine stimulation (conditioned stimulus, CS) and corneal airpuff (unconditioned stimulus, US). Pontine stimulation thresholds dropped dramatically after training and returned to baseline levels following extinction, whereas interpositus thresholds and input-output functions remained stable across training sessions. Learning rate, magnitude of threshold change, and electrode placements were correlated. Pontine projection patterns to the cerebellum were confirmed with retrograde labeling techniques. These results add to the body of literature suggesting that the pons relays CS information to the cerebellum and provide further evidence of synaptic plasticity in the cerebellar network.
Animals↗
Classical eyeblink conditioning in two strains of mice: conditioned responses, sensitization, and spontaneous eyeblinks.
Conditioned eyeblink responses (CRs), sensitization, and spontaneous eyeblinks were studied in C57BL/6J and BALB/c mice. Both strains of mice acquired CRs during 10 days of classical delay eyeblink conditioning. The BALB/c mice reached a higher asymptotic CR level than the C57BL/6J mice. The CRs were extinguished and recovered in both strains following conditioned stimulus-alone and paired conditioned stimulus-unconditioned stimulus training. During 10 days of explicitly unpaired training, the control groups showed no signs of sensitization and low incidence of spontaneous eyeblinks. When switched to paired training, the unpaired groups exhibited significant conditioned inhibition. These results suggest that strain differences must be considered in experimental design and data interpretation for these basic aspects of associative learning and memory.
Analysis of Variance↗
Monoamines and memory in mutant mice.
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Animals↗
Feedback and self-efficacy, arousal, and performance of introverts and extraverts.
Research has suggested that introverts and extraverts differ in their responses to performance feedback. The present study examined the effect on introverts and extraverts of a short-term memory task. Subjects (ns = 8) were randomly assigned to one of three feedback conditions: positive, negative, or control. On posttest, introverts performed better than extraverts regardless of feedback condition. These findings suggest that individual differences in introversion-extraversion mediate differences in performance through subjective arousal, namely, state-anxiety.
Adult↗
Impaired motor coordination and persistent multiple climbing fiber innervation of cerebellar Purkinje cells in mice lacking Galphaq.
Mice lacking the alpha-subunit of the heterotrimeric guanine nucleotide binding protein Gq (Galphaq) are viable but suffer from ataxia with typical signs of motor discoordination. The anatomy of the cerebellum is not overtly disturbed, and excitatory synaptic transmission from parallel fibers to cerebellar Purkinje cells (PCs) and from climbing fibers (CFs) to PCs is functional. However, about 40% of adult Galphaq mutant PCs remain multiply innervated by CFs because of a defect in regression of supernumerary CFs in the third postnatal week. Evidence is provided suggesting that Galphaq is part of a signaling pathway that is involved in the elimination of multiple CF innervation during this period.
Age Factors↗
Time-dependent blockade of STP and LTP in hippocampal slices following acute stress in mice.
The characteristics of short-term potentiation (STP) and long-term potentiation (LTP) in the CA1 region of hippocampal slices were determined at various times following exposure to acute stress produced by restraint and tail-shock in mice. In slices prepared from control animals, theta-burst stimulation resulted in a large increase in evoked field excitatory postsynaptic potentials (EPSPs) amplitude and slope that remained stable at least up to 30 min after stimulation. Slices prepared 1 h after stress exhibited a marked decrease in the extent of both STP and LTP. STP and LTP magnitude were still significantly decreased 24 h after stress exposure and were completely restored to control levels by 48 h. These results provide evidence for a reversible impairment of STP and LTP in CA1 following an acute episode of stress, and suggest that stress activates processes different from those activated by LTP-inducing stimuli.
Animals↗
Selective enhancement of emotional, but not motor, learning in monoamine oxidase A-deficient mice.
Mice deficient in monoamine oxidase A (MAOA), an enzyme that metabolizes monoamines such as norepinephrine and serotonin, have elevated norepinephrine and serotonin levels in the frontal cortex, hippocampus, and cerebellum, compared with normal wild-type mice. Since monoamines in these areas are critically involved in a variety of behaviors, we examined learning and memory (using emotional and motor tasks) in MAOA mutant mice. The MAOA-deficient mice exhibited significantly enhanced classical fear conditioning (freezing to both tone and contextual stimuli) and step-down inhibitory avoidance learning. In contrast, eyeblink conditioning was normal in these mutant mice. The female MAOA-deficient mice also displayed normal species-typical maternal behaviors (nesting, nursing, and pup retrieval). These results suggest that chronic elevations of monoamines, due to a deletion of the gene encoding MAOA, lead to selective alterations in emotional behavior.
Animals↗
Disruption of trace conditioning of the nictitating membrane response in rabbits by central cholinergic blockade.
Central muscarinic cholinergic involvement in classical conditioning of eyeblink responses was determined in trace and delay paradigms. Rabbits were trained on a trace procedure in which a 250-ms tone conditioned stimulus (CS) and a 100-ms air-puff unconditioned stimulus (UCS) were presented with a 500-ms trace interval. Each training session day consisted of ten tone alone, ten air-puff alone and 80 paired CS-UCS trials. Scopolamine hydrochloride at doses of 0.03 and 0.1 mg/0.5 ml per kg, s.c. dose-dependently disrupted acquisition of conditioned responses. Rabbits that were treated with scopolamine and failed to learn showed a gradual increase in conditioned responses during an additional training period with saline injections and no transfer from earlier training. Scopolamine methyl bromide, which does not appreciably cross the blood-brain barrier, showed no effects in the trace conditioning paradigm at a dose of 0.1 mg/kg, s.c., indicating central cholinergic blockade is responsible for the suppressive effect of scopolamine. Scopolamine hydrochloride at a dose of 0.1 mg/kg, s.c. did not block acquisition in the delay procedure with a 250-ms inter-stimulus interval, although the rate of acquisition was somewhat reduced by the drug. These data are the first to demonstrate that classical conditioning of the eyeblink response in the trace procedure is highly sensitive to central cholinergic deficits.
Animals↗
Associative learning.
This chapter reviews evidence demonstrating the essential role of the cerebellum and its associated circuitry in the learning and memory of classical conditioning of discrete behavioral responses (e.g., eyeblink, limb flexion, head turn). It now seems conclusive that the memory traces for this basic category of associative learning are formed and stored in the cerebellum. Lesion, neuronal recording, electrical microstimulation, and anatomical procedures have been used to identify the essential conditioned stimulus (CS) circuit, including the pontine mossy fiber projections to the cerebellum; the essential unconditioned stimulus (US) reinforcing or teaching circuit, including neurons in the inferior olive (dorsal accessory olive) projecting to the cerebellum as climbing fibers; and the essential conditioned response (CR) circuit, including the interpositus nucleus, its projection via the superior cerebellar peduncle to the magnocellular red nucleus, and rubral projections to premotor and motor nuclei. Each major component of the eyeblink CR circuit was reversibly inactivated both in trained animals and over the course of training. In all cases in trained animals, inactivation abolished the CR (and the UR as well when motor nuclei were inactivated). When animals were trained during inactivation (and not exhibiting CRs) and then tested without inactivation, animals with inactivation of the motor nuclei, red nucleus, and superior peduncle had fully learned, whereas animals with inactivation of a very localized region of the cerebellum (anterior interpositus and overlying cortex) had not learned at all. Consequently, the memory traces are formed and stored in the cerebellum. Several alternative possibilities are considered and ruled out. Both the cerebellar cortex and the interpositus nucleus are involved in the memory storage process, suggesting that a phenomenon-like long-term depression (LTD) is involved in the cerebellar cortex and long-term potentiation (LTP) is involved in the interpositus. The experimental findings reviewed in this chapter provide perhaps the first conclusive evidence for the localization of a basic form of memory storage to a particular brain region, namely the cerebellum, and indicate that the cerebellum is indeed a cognitive machine.
Animals↗