A nitric oxide-independent and beta-adrenergic receptor-sensitive form of metaplasticity limits theta-frequency stimulation-induced LTP in the hippocampal CA1 region

The induction of long-term potentiation (LTP) and long-term depression (LTD) at excitatory synapses in the hippocampus can be strongly modulated by patterns of synaptic stimulation that otherwise have no direct effect on synaptic strength. Likewise, patterns of synaptic stimulation that induce LTP or LTD not only modify synaptic strength but can also induce lasting changes that regulate how synapses will respond to subsequent trains of stimulation. Collectively known as metaplasticity, these activity-dependent processes that regulate LTP and LTD induction allow the recent history of synaptic activity to influence the induction of activity-dependent changes in synaptic strength and may thus have an important role in information storage during memory formation. To explore the cellular and molecular mechanisms underlying metaplasticity, we investigated the role of metaplasticity in the induction of LTP by υ-frequency (5-Hz) synaptic stimulation in the hippocampal CA1 region. Our results show that brief trains of υ-frequency stimulation not only induce LTP but also activate a process that inhibits the induction of additional LTP at potentiated synapses. Unlike other forms of metaplasticity, the inhibition of LTP induction at potentiated synapses does not appear to arise from activity-dependent changes in NMDA receptor function, does not require nitric oxide signaling, and is strongly modulated by β-adrenergic receptor activation. Together with previous findings, our results indicate that mechanistically distinct forms of metaplasticity regulate LTP induction and suggest that one way modulatory transmitters may act to regulate synaptic plasticity is by modulating metaplasticity.     

Defense reaction elicited by microinjection of kainic acid into the medial hypothalamus of the rat: antagonism by a GABAA receptor agonist.

Electrical stimulation of either the midbrain central gray or the medial hypothalamus induces a defense reaction in the rat, characterized mainly by increased locomotion, rearing, and leaping. However, microinjection of the excitatory amino acid glutamate was effective only in the former region. Because excitatory amino acids do not depolarize axons of passage, it was suggested that the hypothalamus is devoid of soma/dendrites of neurons commanding the defense reaction. In the present study, we show that a subtoxic dose (60 pmol) of another excitatory amino acid, kainic acid, injected into the medial hypothalamus significantly enhanced locomotion and rearing of Wistar rats systematically observed in an open field. Similar behavioral changes have been reported following microinjection of drugs impairing GABAergic neurotransmission. Local pretreatment with the GABAA receptor agonist THIP (2 nmol) blocked the effect of kainic acid. Therefore, the medial hypothalamus of the rat seems to contain a population of neuronal cell bodies commanding the defense reaction, which is activated by excitatory amino acids and tonically inhibited by GABAergic fibers.     

Cognitive disruption and altered hippocampus synaptic function in Reelin haploinsufficient mice

The heterozygote reeler mouse (HRM) shows many neuroanatomical and biochemical features that are also present in some human cognitive disorders, such as schizophrenia. In the present study, hippocampal dependent plasticity and cognitive function of the HRM were characterized in detail in an attempt to reveal phenotypic functional differences that result from Reelin haploinsufficiency. The HRM and wild type mice show similar levels of overall activity, coordination, thermal nociception, startle responses, and anxiety-like behavior. In addition, both genotypes show similar shock threshold, identical cued freezing behavior and comparable spatial learning in Morris water maze tasks. However, a significant reduction in contextual fear conditioned learning was observed in the HRM. Electrophysiological studies in hippocampal CA1 synapses revealed a plethora of differences between genotypes. The HRM exhibits reduced field excitatory postsynaptic potentials in responses to similar synaptic inputs, lowered paired pulse facilitation ratio and impaired long-term depression and tetanus-induced long-term potentiation (LTP). Also, deficits were detected in LTP elicited by theta burst stimulation or by a whole cell pairing protocol. These physiologic differences could not be accounted for by changes in the overall amount of glutamate receptor subunits. In addition, it was determined that network-driven excitatory and inhibitory activities recorded in CA1 pyramidal neurons showed that the HRM had comparable amplitude and frequency of spontaneous excitatory postsynaptic currents, but a marked reduction in spontaneous inhibitory postsynaptic currents. Thus, the HRM exhibits a specific hippocampal-dependent learning deficit accompanied with a pronounced impairment of hippocampal plasticity and functional inhibitory innervation.     

Altered daylength affects dendritic structure in a song-related brain region in red-winged blackbirds.

Substantial neural and behavioral plasticity occurs in the avian song system in adulthood. Changes in the volume of one of the song control nuclei, robustus archistriatalis (RA), have been associated with seasonal changes in singing behavior in adult canaries (Serinus canarius) and red-winged blackbirds (Agelaius phoeniceus). The present work assessed the effects of changed daylength on dendritic morphology in RA in adult male red-winged blackbirds. Brains from hand-reared red-winged blackbirds maintained on long days or long days followed by short days were stained with a Golgi-Cox procedure. Dendritic morphology and spine density of type IV neurons from nucleus RA were compared between long and short day birds. Neurons from short day birds have smaller dendritic fields than neurons from long day birds, with the difference greatest for distal dendrites. In addition, the density of dendritic spines is significantly smaller for neurons from short day birds. Together, these changes result in the loss of approximately 40% of the spines on this neuron class. In previous work in adult female canaries, external testosterone administration has been shown to be associated with increases in dendritic field size and synapse number. The similarity of the neuronal changes in RA that are associated with the two sorts of manipulations suggest that some consequences of altered daylength are mediated by changes in the levels of gonadal steroids.     

Low-frequency stimulation induces a pathway-specific late phase of LTP in the amygdala that is mediated by PKA and dependent on protein synthesis

Activity-dependent changes in synaptic efficacy are thought to be the key cellular mechanism for the formation and storage of both explicit and implicit memory. Different patterns of stimulation can elicit different changes in the efficiency on excitatory synaptic transmission. Here, we examined the synaptic changes in the amygdala of adult mice produced by low-frequency stimulation (1 Hz, 15 min, LFS). We first compared the synaptic changes induced by LFS in three different synaptic pathways of amygdala: cortical–lateral amygdala, thalamic–lateral amygdala, and lateral–basolateral amygdala pathways. We find that the plastic changes induced by LFS are different between synaptic pathways. Low-frequency stimulation selectively elicits a slow onset and protein synthesis-dependent late-phase LTP in the cortical–lateral amygdala pathway, but not in the thalamic–lateral or lateral–basolateral pathways. We next analyzed LTP induced by LFS in the cortical–lateral amygdala pathway and found that three PKA-coupling neurotransmitter receptors are involved: 5-HT4, Dopamine D1, and β-adrenergic receptors. Antagonists of these receptors block the LFS L-LTP, but the effects of agonists of these receptors are clearly different. These results indicate that the threshold for the induction of LFS L-LTP is different among these pathways and that the maintenance of LFS L-LTP requires a cross-talk among multiple neurotransmitters.     

Regulation of low-threshold afferent activity may contribute to short-term habituation in Aplysia californica

The goal of this study was to characterize the contribution of a population of low-threshold mechanoreceptors to short-term habituation of siphon-elicited reflex responses in Aplysia californica. Since the location of their somata is unknown, we refer to them as the Unidentified Low-Threshold mechanoreceptors (ULTs). The ULTs operate in parallel to the higher-threshold and well-characterized LE sensory neurons, yet little is known regarding their contribution to behavioral plasticity. Using extracellular recordings from the siphon nerve, we found that habituation training that favors ULT activation resulted in a significant decrease in afferent activity at training intervals up to 1 min per stimulus (1 min ISI). To determine how this reduction impacts responses at other sites of the reflex network, we used intracellular recordings to measure training-induced changes in either L29 excitatory interneurons or LFS siphon motor neurons. With a 30s ISI, changes at both locations were training site-specific and matched the rate of change of afferent activity, implicating regulated sensory activity as a primary mechanism. With a shorter training interval (1s ISI), site-specificity of training was not observed in the L29s, but was still preserved in the motor neurons. For both, the rate of change during training was faster than the rate of change of afferent activity. Taken together, we conclude that regulation of low-threshold sensory neuron activity can play a significant role in short-term habituation, but other network processes may be recruited at more rapid training intervals.     

Vagus nerve stimulation: a new form of therapeutic brain stimulation

Although the vagus nerve has traditionally been considered to perform efferent functions, in reality it performs significant afferent functions as well, carrying information from the body, head, and neck to the brain. Preliminary studies examining this afferent activity led to the theory that vagus nerve stimulation (VNS) could successfully control seizure activity in persons who are refractory to antiepileptic medications. Unlike other forms of brain stimulation, VNS is unable to directly stimulate multiple discrete areas of the brain; however, through several pathways, it is able to relay sensory information to higher brain regions. An implantable VNS device known as the VNSTM NeuroCybernetic Prosthesis (NCP) System has been used in approximately 9,000 epilepsy patients in Europe and the United States since 1994. The implant has reduced seizure frequency by an average of 25% to 30%, with minimal side effects. Studies underway are also showing some degree of success in the management of treatment-refractory depression. The future efficacy of the implantable system in other disorders may depend on whether the implant can be more precisely focused to affect different brain regions. Research in this area is underway.     

Development of Multiple Movement Representations With Practice: Specificity Versus Flexibility

The question addressed in the present experiment was whether an individual who practices a task under different conditions of afferent information develops different movement representations, each of which is based on the most accurate source of afferent information for movement control. In Experiment 1, participants (N = 23) performed a manual aiming movement in a target-only condition for 520 trials before performing in a normal vision condition for an equivalent amount of practice. Control groups performed all practice trials in either a normal vision or a target-only condition. The results revealed that the movement representation developed in the initial (target-only) practice phase remained accessible for movement planning and control. The results of Experiment 2 indicated, however, that participants did not maintain such a representation when their initial practice in the target-only condition was reduced (40 or 160 trials) before they had extensive practice in normal vision. Those results indicate that extensive practice in a target-only and then in a normal vision condition enables an individual to plan and control his or her movement on the basis of the most efficient source of available afferent information. Because visual afferent information provides optimal information for ensuring movement accuracy, however, if initial practice in the target-only condition is only modest or moderate it is likely that that information source will progressively dominate all other sources of afferent information for movement planning and control.     

Development of multiple movement representations with practice: specificity versus flexibility

The question addressed in the present experiment was whether an individual who practices a task under different conditions of afferent information develops different movement representations, each of which is based on the most accurate source of afferent information for movement control. In Experiment 1, participants (N = 23) performed a manual aiming movement in a target-only condition for 520 trials before performing in a normal vision condition for an equivalent amount of practice. Control groups performed all practice trials in either a normal vision or a target-only condition. The results revealed that the movement representation developed in the initial (target-only) practice phase remained accessible for movement planning and control. The results of Experiment 2 indicated, however, that participants did not maintain such a representation when their initial practice in the target-only condition was reduced (40 or 160 trials) before they had extensive practice in normal vision. Those results indicate that extensive practice in a target-only and then in a normal vision condition enables an individual to plan and control his or her movement on the basis of the most efficient source of available afferent information. Because visual afferent information provides optimal information for ensuring movement accuracy, however, if initial practice in the target-only condition is only modest or moderate it is likely that that information source will progressively dominate all other sources of afferent information for movement planning and control.     

Spatiotemporal dynamics of long-term potentiation in rat insular cortex revealed by optical imaging

Long-term potentiation (LTP) of the gustatory cortex (GC), a part of the insular cortex (IC) around the middle cerebral artery, is a key process of gustatory learning and memory, including conditioned taste aversion learning. The rostral (rGC) and caudal GC (cGC) process different tastes; the rGC responds to hedonic and the cGC responds to aversive tastes. However, plastic changes of spatial interaction of excitatory propagation between the rGC and cGC remain unknown. The present study aimed to elucidate spatiotemporal profiles of excitatory propagation, induced by electrical stimulation (five train pulses) of the rGC/cGC before and after LTP induction, using in vivo optical imaging with a voltage-sensitive dye. We demonstrated that tetanic stimulation of the cGC induced long-lasting expansion of the excitation responding to five train stimulation of the cGC, and an increase in amplitude of optical signals in the IC. Excitatory propagation after LTP induction spread preferentially toward the rostral IC: the length constant (λ) of excitation, obtained by fitting optical signals with a monoexponential curve, was increased to 121.9% in the rostral direction, whereas λ for the caudal, dorsal, and ventral directions were 48.9%, 44.2%, and 62.5%, respectively. LTP induction was prevented by pre-application of D-APV, an NMDA receptor antagonist, or atropine, a muscarinic receptor antagonist, to the cortical surface. In contrast, rGC stimulation induced only slight LTP without direction preference. Considering the different roles of the rGC and cGC in gustatory processing, these characteristic patterns of LTP in the GC may be involved in a mechanism underlying conversion of palatability.     

Transcranial direct current stimulation and visual perception

Membrane potentials and spike sequences represent the basic modes of cerebral information processing. Both can be externally modulated in humans by quite specific techniques: transcranial direct current stimulation (tDCS) and repetitive transcranial magnetic stimulation (rTMS). These methods induce reversible circumscribed cortical excitability changes, either excitatory or inhibitory, outlasting stimulation in time. Experimental pharmacological interventions may selectively enhance the duration of the aftereffects. Whereas rTMS induces externally triggered changes in the neuronal spiking pattern and interrupts or excites neuronal firing in a spatially and temporally restricted fashion, tDCS modulates the spontaneous firing rates of neurons by changing resting-membrane potential. The easiest and most common way of evaluating the cortical excitability changes is by applying TMS to the motor cortex, since it allows reproducible quantification through the motor-evoked potential. Threshold determinations at the visual cortex or psychophysical methods usually require repeated and longer measurements and thus more time for each data set. Here, results derived from the use of tDCS in visual perception, including contrast as well as motion detection and visuo-motor coordination and learning, are summarised. It is demonstrated that visual functions can be transiently altered by tDCS, as has been shown for the motor cortex previously. Up- and down-regulation of different cortical areas by tDCS is likely to open a new branch in the field of visual psychophysics.     

Decrement of the Müller-Lyer illusion with saccadic and tracking eye movements

Subjects viewed the Müller-Lyer illusion, making either saccadic or smooth tracking eye movements between the apexes of the arrow heads. The decrement in the magnitude of the illusion was significantly greater for Ss in the saccadic viewing condition. Saccadic and smooth tracking eye movements are separately controlled,and information about eye position is more readily available from the efferent signals issued to control a saccadic eye movement. The experimental findings were consistent with the hypothesis that Ss in the saccadic condition learned a new afferent efferent association. The results support a theory that visual perception is determined by efferent readiness activated by visual afferent stimulation.     

Adrenergic stimulation of the rat diencephalon and its effect on food intake and hoarding activity

The diencephalic area most sensitive to microinjections of noradrenaline lay outside the area of the lateral hypothalamus in which feeding can be produced by electrical stimulation. Injection of either area, including injections that caused increased feeding, failed to have any effect on hoarding activity. Since hoarding can be elicited both by food deprivation and by electrical stimulation of the lateral hypothalamus, these findings indicate biochemical, anatomical and motivational differences between the central feeding mechanism sensitive to adrenergic stimulation, and that responding to electrical stimulation or nutritional depletion. The former mechanism may be disinhibitory; the latter, excitatory.     

Synapse specificity of long-term potentiation breaks down with aging

Memory shows age-related decline. According to the current prevailing theoretical model, encoding of memories relies on modifications in the strength of the synapses connecting the different cells within a neuronal network. The selective increases in synaptic weight are thought to be biologically implemented by long-term potentiation (LTP). Here, we report that tetanic stimulation of afferent fibers in slices from 12-mo-old mice triggers an LTP not restricted to the activated synapses. This phenomenon, which can be anticipated to hinder memory encoding, is suppressed by blocking either L-type Ca(++) channels or Ca(++)-induced Ca(++) release, both well known to become disregulated with aging.     

Changes in somatosensory evoked potentials and Hoffmann reflexes during fast isometric contraction of foot plantarflexor in humans

In the present study, the extent to which the early component of somatosensory evoked potentials (SEPs) and the Hoffmann (H-) reflex induced by stimulation of the posterior tibial nerve are altered during the ascending and descending phases of fast plantarflexion was investigated. SEPSs and H-reflex of the soleus following tibial nerve stimulation were examined during fast plantarfiexion when performed by nine normal subjects. The analyses focused on differences in amplitude modulation of the P30-P40 component of SEP and the H-reflex between the ascending and descending phases of full-wave rectified and averaged soleus electromyographic (EMG) activity. The H-reflex amplitude was significantly increased and decreased during the ascending and descending phases more than under resting control conditions, respectively. The reduction of SEP amplitude was 49% for the ascending phase and 83% for the descending phases with respect to the resting situation. Modulation of SEP during the ascending and descending phases was robustly retained even during ischemic nerve blockade of large diameter afferent fibers. These findings suggest that the transmission of afferent inputs from muscle spindles to motoneurons and to the somatosensory cortex during fast isometric contraction of the plantar flexor is regulated in a time-dependent fashion by descending commands.     

The organization of motivated and conditional reflex processes

Recent observations on the plasticity of brain and behavior relationships indicate that the temporary connections between environmental and neuroanatomical substrates have tremendous specificity but at the same time are very plastic. Establishment of a conditional reflex by stimulation of the hippocampal pyramidal layer and/or the mesencephalic reticular formation did not interfere with the differential stimulation of very near points in the same structures. These correlations between brain and behavior confirmed the earlier belief that the development of temporary connections between environment and brain is an elementary process of the central nervous system. Complex behavioral functions are organized through both neuronal and humoral afferentation. Data accumulated recently indicate that the descending forebrain influence is inhibitory in the brain stem and diencephalon and controls the sensory input in a somatomotor-specific and situation-specific manner. Humoral factors affecting thresholds can change the dynamic equilibrium existing between ascending excitatory and descending inhibitory systems; these alterations always follow the rule of situation and somatomotor specificity.     

Morphological changes in dendritic spines of Purkinje cells associated with motor learning

Experience-dependent changes of spine structure and number may contribute to long-term memory storage. Although several studies demonstrated structural spine plasticity following associative learning, there is limited evidence associating motor learning with alteration of spine morphology. Here, we investigated this issue in the cerebellar Purkinje cells using high voltage electron microscopy (HVEM). Adult rats were trained in an obstacle course, demanding significant motor coordination to complete. Control animals either traversed an obstacle-free runway or remained sedentary. Quantitative analysis of spine morphology showed that the density and length of dendritic spines along the distal dendrites of Purkinje cells were significantly increased in the rats that learned complex motor skills compared to active or inactive controls. Classification of spines into shape categories indicated that the increased spine density and length after motor learning was mainly attributable to an increase in thin spines. These findings suggest that motor learning induces structural spine plasticity in the cerebellar Purkinje neurons, which may play a crucial role in acquiring complex motor skills.     

Perirhinal cortex muscarinic receptor blockade impairs taste recognition memory formation

The relevance of perirhinal cortical cholinergic and glutamatergic neurotransmission for taste recognition memory and learned taste aversion was assessed by microinfusions of muscarinic (scopolamine), NMDA (AP-5), and AMPA (NBQX) receptor antagonists. Infusions of scopolamine, but not AP5 or NBQX, prevented the consolidation of taste recognition memory using attenuation of neophobia as an index. In addition, learned taste aversion in both short- and long-term memory tests was exclusively impaired by scopolamine. These data provide neurochemical support for the theory that cholinergic activity of the perirhinal cortex participates in the formation of the taste memory trace and that it is independent of the NMDA and AMPA receptor activity. These results support the idea that cholinergic neurotransmission in the perirhinal cortex is also essential for acquisition and consolidation of taste recognition memory.     

Effects of callosal lesions in a model of letter perception

During cognitive tasks, the cerebral hemispheres cooperate, compete, and in general, interact via the corpus callosum. Although behavioral studies in normal and split-brain subjects have revealed a great deal about the transcallosal exchange of information, a fundamental question remains unanswered and controversial: Are transcallosal interhemispheric influences primarily excitatory or inhibitory? In this context, we examined the effects of simulating sectioning of the corpus callosum in a computational model of visual letter recognition. Differences were found, following simulated callosal sectioning, in the performance of each individual hemisphere, in the mean activation levels of hemispheres, and in the specific patterns of activity, depending on the nature of the callosal influences. Together with other recent computational modeling results, the findings are most consistent with the hypothesis that transcallosal influences are predominantly excitatory, and they suggest measures that could be examined in future experimental studies to help resolve this issue.     

The function of dendritic spines: a review of theoretical issues

The discovery of dendritic spines in the late nineteenth century has prompted nearly 90 years of speculation about their physiological importance. Early observations that bulbous spine heads had very close approximations with the axon terminals of other neurons, confirmed later by ultrastructural study, led to ideas that spines enhance dendritic surface areas for making synaptic contacts. More recent application of cable and core-conductor theory to the anatomical study of spines has raised a number of new ideas about spine function. One important issue was derived from the theoretical treatment of spines as tiny dendrites with much higher input resistances than those of the larger parent dendrites. The high spine-stem resistance results in relative electrical isolation of the spine head; this causes large local depolarizations in the spine head. Several theoretical studies have also shown that if the spine-head input resistances are substantially higher than those of the parent dendrites, spines have the potential for modulating a host of biochemical and biophysical processes that might regulate synaptic efficacy. Empirical studies have documented that spine heads increase rapidly in size after afferent projections have been stimulated electrically and after animals have engaged in a single bout of ecologically important behavioral activity. Such spine head enlargement dilates the portion of the spine stem adjacent to the spine head and this process shortens the spine stem without appreciably altering overall spine length. Theoretical study shows that spine-stem shortening lowers the spine-head input resistance relative to the branch input resistance. This reduction in input resistance can enhance the transfer of electrical charge from the spine head to the parent dendrite, especially when the synaptic conductance is large relative to the spine-head input conductance. Spine-stem shortening also lowers the peak transient membrane potential in the spine head and this factor could delimit Ca2+ influx into the spine head via voltage-dependent Ca2+ channels. The modulation of Ca2+ influx by spine-stem shortening has the potential for regulating Ca2+-sensitive enzymatic activity in the spine head that could affect phosphorylation of cytoskeletal proteins maintaining spine shape and phosphorylation of proteins in the postsynaptic density. Finally, theoretical findings are described that examine the effects of voltage-dependent inward-current channels in the spine head and their ability to amplify the charge transfer due to transmitter-dependent synaptic conductances.