Brain-Generated 17ß-Estradiol Modulates Long-Term Synaptic Plasticity in the Primary Auditory Cortex of Adult Male Rats.

Neuron-derived 17ß-estradiol (E2) alters synaptic transmission and plasticity in brain regions with endocrine and non-endocrine functions. Investigations into a modulatory role of E2 in synaptic activity and plasticity have mainly focused on the rodent hippocampal formation. In songbirds, E2 is synthesized by auditory forebrain neurons and promotes auditory signal processing and memory for salient acoustic stimuli; however, the modulatory effects of E2 on memory-related synaptic plasticity mechanisms have not been directly examined in the auditory forebrain. We investigated the effects of bidirectional E2 manipulations on synaptic transmission and long-term potentiation (LTP) in the rat primary auditory cortex (A1). Immunohistochemistry revealed widespread neuronal expression of the E2 biosynthetic enzyme aromatase in multiple regions of the rat sensory and association neocortex, including A1. In A1, E2 application reduced the threshold for in vivo LTP induction at layer IV synapses, whereas pharmacological suppression of E2 production by aromatase inhibition abolished LTP induction at layer II/III synapses. In acute A1 slices, glutamate and γ-aminobutyric acid (GABA) receptor-mediated currents were sensitive to E2 manipulations in a layer-specific manner. These findings demonstrate that locally synthesized E2 modulates synaptic transmission and plasticity in A1 and suggest potential mechanisms by which E2 contributes to auditory signal processing and memory.

The history of long-term potentiation as a memory mechanism: Controversies, confirmation, and some lessons to remember.

The discovery of long-term potentiation (LTP) provided the first, direct evidence for long-lasting synaptic plasticity in the living brain. Consequently, LTP was proposed to serve as a mechanism for information storage among neurons, thus providing the basis for the behavioral and psychological phenomena of learning and long-term memory formation. However, for several decades, the LTP-memory hypothesis remained highly controversial, with inconsistent and contradictory evidence providing a barrier to its general acceptance. This review summarizes the history of these early debates, challenges, and experimental strategies (successful and unsuccessful) to establish a link between LTP and memory. Together, the empirical evidence, gathered over a period of about four decades, strongly suggests that LTP serves as one of the mechanisms affording learning and memory storage in neuronal circuits. Notably, this body of work also offers some important lessons that apply to the broader fields of behavioral and cognitive neuroscience. As such, the history of LTP as a learning mechanism provides valuable insights to neuroscientists exploring the relations between brain and psychological states.

Abuse potential and adverse cognitive effects of mitragynine (kratom).

Mitragynine is the major psychoactive alkaloid of the plant kratom/ketum. Kratom is widely used in Southeast Asia as a recreational drug, and increasingly appears as a pure compound or a component of 'herbal high' preparations in the Western world. While mitragynine/kratom may have analgesic, muscle relaxant and anti-inflammatory effects, its addictive properties and effects on cognitive performance are unknown. We isolated mitragynine from the plant and performed a thorough investigation of its behavioural effects in rats and mice. Here we describe an addictive profile and cognitive impairments of acute and chronic mitragynine administration, which closely resembles that of morphine. Acute mitragynine has complex effects on locomotor activity. Repeated administration induces locomotor sensitization, anxiolysis and conditioned place preference, enhances expression of dopamine transporter- and dopamine receptor-regulating factor mRNA in the mesencephalon. While there was no increase in spontaneous locomotor activity during withdrawal, animals showed hypersensitivity towards small challenging doses for up to 14 days. Severe somatic withdrawal signs developed after 12 hours, and increased level of anxiety became evident after 24 hours of withdrawal. Acute mitragynine independently impaired passive avoidance learning, memory consolidation and retrieval, possibly mediated by a disruption of cortical oscillatory activity, including the suppression of low-frequency rhythms (delta and theta) in the electrocorticogram. Chronic mitragynine administration led to impaired passive avoidance and object recognition learning. Altogether, these findings provide evidence for an addiction potential with cognitive impairments for mitragynine, which suggest its classification as a harmful drug.

Age-Dependent Switch of the Role of Serotonergic 5-HT1A Receptors in Gating Long-Term Potentiation in Rat Visual Cortex In Vivo.

The rodent primary visual cortex (V1) is densely innervated by serotonergic axons and previous in vitro work has shown that serotonin (5-HT) can modulate plasticity (e.g., long-term potentiation (LTP)) at V1 synapses. However, little work has examined the effects of 5-HT on LTP under in vivo conditions. We examined the role of 5-HT on LTP in V1 elicited by theta burst stimulation (TBS) of the lateral geniculate nucleus in urethane-anesthetized (adult and juvenile) rats. Thalamic TBS consistently induced potentiation of field postsynaptic potentials (fPSPs) recorded in V1. While 5-HT application (0.1-10 mM) itself did not alter LTP levels, the broad-acting 5-HT receptor antagonists methiothepin (1 mM) resulted in a clear facilitation of LTP in adult animals, an effect that was mimicked by the selective 5-HT1A receptor antagonist WAY 100635 (1 mM). Interestingly, in juvenile rats, WAY 100635 application inhibited LTP, indicative of an age-dependent switch in the role of 5-HT1A receptors in gating V1 plasticity. Analyses of spontaneous electrocorticographic (ECoG) activity in V1 indicated that the antagonist-induced LTP enhancement was not related to systematic changes in oscillatory activity in V1. Together, these data suggest a facilitating role of 5-HT1A receptor activation on LTP in the juvenile V1, which switches to a tonic, inhibitory influence in adulthood.

Potential Role of Synaptic Activity to Inhibit LTD Induction in Rat Visual Cortex.

Long-term depression (LTD), a widely studied form of activity-dependent synaptic plasticity, is typically induced by prolonged low-frequency stimulation (LFS). Interestingly, LFS is highly effective in eliciting LTD in vitro, but much less so under in vivo conditions; the reasons for the resistance of the intact brain to express LTD are not well understood. We examined if levels of background electrocorticographic (ECoG) activity influence LTD induction in the thalamocortical visual system of rats under very deep urethane anesthesia, inducing a brain state of reduced spontaneous cortical activity. Under these conditions, LFS applied to the lateral geniculate nucleus resulted in LTD of field postsynaptic potentials (fPSPs) recorded in the primary visual cortex (V1). Pairing LFS with stimulation of the brainstem (pedunculopontine) reticular formation resulted in the appearance of faster, more complex activity in V1 and prevented LTD induction, an effect that did not require muscarinic or nicotinic receptors. Reticular stimulation alone (without LFS) had no effect on cortical fPSPs. These results show that excitation of the brainstem activating system blocks the induction of LTD in V1. Thus, higher levels of neural activity may inhibit depression at cortical synapses, a hypothesis that could explain discrepancies regarding LTD induction in previous in vivo and in vitro work.

Effects of Patterned Sound Deprivation on Short- and Long-Term Plasticity in the Rat Thalamocortical Auditory System In Vivo.

Postnatal sensory experience plays a significant role in the maturation and synaptic stabilization of sensory cortices, such as the primary auditory cortex (A1). Here, we examined the effects of patterned sound deprivation (by rearing in continuous white noise, WN) during early postnatal life on short- and long-term plasticity of adult male rats using an in vivo preparation (urethane anesthesia). Relative to age-matched control animals reared under unaltered sound conditions, rats raised in WN (from postnatal day 5 to 50-60) showed greater levels of long-term potentiation (LTP) of field potentials in A1 induced by theta-burst stimulation (TBS) of the medial geniculate nucleus (MGN). In contrast, analyses of short-term plasticity using paired-pulse stimulation (interstimulus intervals of 25-1000 ms) did not reveal any significant effects of WN rearing. However, LTP induction resulted in a significant enhancement of paired-pulse depression (PPD) for both rearing conditions. We conclude that patterned sound deprivation during early postnatal life results in the maintenance of heightened, juvenile-like long-term plasticity (LTP) into adulthood. Further, the enhanced PPD following LTP induction provides novel evidence that presynaptic mechanisms contribute to thalamocortical LTP in A1 under in vivo conditions.

The lateral septum as a regulator of hippocampal theta oscillations and defensive behavior in rats.

Hippocampal theta oscillations are linked to various processes, including locomotion, learning and memory, and defense and affect. The lateral septum (LS) has been implicated in the generation of the hippocampal theta rhythm, but its precise role in this process is not well understood. Here, we investigated the effects of direct pharmacological inhibition or disinhibition of the dorsal LS (dLS) on the frequency of hippocampal theta activity elicited by stimulation of the reticular formation in urethane-anesthetized rats. We found that bilateral infusions of the GABAA receptor agonist muscimol into the dLS significantly increased theta frequency. Strikingly, intra-dLS infusions of the GABAA receptor antagonist GABAzine largely abolished reticularly elicited theta activity. We also locally injected these same compounds into the medial septum (MS) to test for neuroanatomical specificity. In contrast to the effects seen in the dLS, intra-MS infusions of muscimol had no effect on theta frequency, whereas intra-MS infusions of GABAzine increased theta frequency. Given the hypothesized role of hippocampal theta in behavioral defense, we also examined the effects of intra-dLS application of muscimol in two models of anxiety, the elevated plus maze and the novelty-induced suppression of feeding paradigm; both tests revealed clear, anxiolytic-like effects following muscimol infusions. The fact that dLS-muscimol increased theta frequency while also reducing anxiety-like behaviors challenges the influential theta suppression model of anxiolysis, which predicts a slowing of theta with anxiolytic compounds. More importantly, the experiments reveal a novel role of the LS, especially its dorsal aspects, as an important gating mechanism for the expression of theta oscillations in the rodent hippocampus.

Occlusion of low-frequency-induced, heterosynaptic long-term potentiation in the rat hippocampus in vivo following spatial training.

Recent work has shown that some low-frequency stimulation (LFS) protocols can induce long-term potentiation (LTP) at hippocampal synapses. As LFS mimics certain aspects of low-frequency oscillations during slow-wave sleep, LFS-LTP may be relevant to processes of sleep-dependent consolidation. Here, alternating LFS (1 Hz) of heterosynaptic inputs arising in the medial septum and area CA3 induced LTP at hippocampal CA1 synapses of anesthetized rats. Remarkably, this LTP was absent when delivered 3 h, but not 8 or 24 h, after training in the hidden platform version of the Morris water maze, suggesting a time-specific occlusion of LFS-LTP following spatial learning. LTP assessed 3 h after training was intact in yoked swim controls and rats trained in darkness. Visible platform training resulted in heterogeneous effects, with about half of the animals showing LTP occlusion. Pharmacological experiments revealed that N-methyl-d-aspartate (NMDA)-receptor activation was required for both LFS-LTP and the retention of spatial learning. To test whether a learning-related, NMDA-dependent potentiation accounted for the occlusion effect, we blocked NMDA receptors immediately following spatial training. This manipulation reversed LTP occlusion 3 h after training. Together, these experiments indicate a mechanistic overlap between heterosynaptically induced LFS-LTP and processes mediating the consolidation of spatial information at hippocampal synapses.

Behavioral anxiolysis without reduction of hippocampal theta frequency after histamine application in the lateral septum of rats.

Hippocampal theta activity is linked to various processes, including locomotion, learning and memory, and defense and affect (i.e., fear and anxiety). Interestingly, all classes of clinically effective anxiolytics, as well as experimental compounds that decrease anxiety in pre-clinical animal models of anxiety, reduce the frequency of hippocampal theta activity elicited by stimulation of the reticular formation in freely behaving or anesthetized animals. In the present experiments, we found that bilateral histamine infusions (0.5 µg/hemisphere) into the lateral septum (LS) of rats decreased anxiety-like responses in two models of anxiety, the elevated plus maze and novelty-induced suppression of feeding test. Surprisingly, these same infusions significantly increased hippocampal theta frequency elicited by reticular stimulation in urethane-anesthetized rats. In contrast to these findings, additional experiments showed that the clinically effective anxiolytic buspirone (40 mg/kg, i.p.) reduced theta frequency, confirming previous observations. Taken together, the dissociation of behavioral anxiolysis and theta frequency reduction noted here suggest that hippocampal theta frequency is not a direct index of anxiety levels in rodents. Further, the mechanisms underlying the behavioral and physiological effects elicited by histamine in the LS require further study.

Chronic fluoxetine treatment suppresses plasticity (long-term potentiation) in the mature rodent primary auditory cortex in vivo.

Several recent studies have provided evidence that chronic treatment with the selective serotonin reuptake inhibitor (SSRI) fluoxetine can facilitate synaptic plasticity (e.g., ocular dominance shifts) in the adult central nervous system. Here, we assessed whether fluoxetine enhances long-term potentiation (LTP) in the thalamocortical auditory system of mature rats, a developmentally regulated form of plasticity that shows a characteristic decline during postnatal life. Adult rats were chronically treated with fluoxetine (administered in the drinking water, 0.2 mg/mL, four weeks of treatment). Electrophysiological assessments were conducted using an anesthetized (urethane) in vivo preparation, with LTP of field potentials in the primary auditory cortex (A1) induced by theta-burst stimulation of the medial geniculate nucleus. We find that, compared to water-treated control animals, fluoxetine-treated rats did not express higher levels of LTP and, in fact, exhibited reduced levels of potentiation at presumed intracortical A1 synapses. Bioactivity of fluoxetine was confirmed by a reduction of weight gain and fluid intake during the four-week treatment period. We conclude that chronic fluoxetine treatment fails to enhance LTP in the mature rodent thalamocortical auditory system, results that bring into question the notion that SSRIs act as general facilitators of synaptic plasticity in the mammalian forebrain.

The Impact of Lunch Timing on Nap Quality.

PURPOSE: Previous research has established that food intake is a biological regulator of the human sleep-wake cycle. As such, the timing of eating relative to sleep may influence the quality of sleep, including daytime naps. Here, we examine whether the timing of lunch (1 h vs. 2 h interval between lunch and a napping opportunity) impacts the quality of an afternoon nap. METHODS: Using a randomized within-subject design over two separate experimental sessions (7 days apart), participants (n = 40, mean age = 25.8 years) consumed lunch 1 h and 2 h prior to an afternoon nap opportunity. Polysomnography and subjective self-reports were used to assess sleep architecture, sleepiness levels, and nap quality. RESULTS: Results revealed no significant differences in subjective ratings of sleep quality and sleepiness, or in sleep architecture (total sleep time, sleep efficiency, sleep onset latency, sleep stages) between the 1 h and 2-h lunch conditions. CONCLUSIONS: All sleep measures were similar when napping followed eating by either 1 h or 2 h, suggesting that eating closer to nap onset may not negatively impact sleep architecture and quality. Future research should continue to identify conditions that improve nap quality, given the well-documented benefits of naps to reduce sleep pressure and improve human performance.

Design of a noninvasive face mask for ocular occlusion in rats and assessment in a visual discrimination paradigm.

The rat visual system is structured such that the large (>90 %) majority of retinal ganglion axons reach the contralateral lateral geniculate nucleus (LGN) and visual cortex (V1). This anatomical design allows for the relatively selective activation of one cerebral hemisphere under monocular viewing conditions. Here, we describe the design of a harness and face mask allowing simple and noninvasive monocular occlusion in rats. The harness is constructed from synthetic fiber (shoelace-type material) and fits around the girth region and neck, allowing for easy adjustments to fit rats of various weights. The face mask consists of soft rubber material that is attached to the harness by Velcro strips. Eyeholes in the mask can be covered by additional Velcro patches to occlude either one or both eyes. Rats readily adapt to wearing the device, allowing behavioral testing under different types of viewing conditions. We show that rats successfully acquire a water-maze-based visual discrimination task under monocular viewing conditions. Following task acquisition, interocular transfer was assessed. Performance with the previously occluded, "untrained" eye was impaired, suggesting that training effects were partially confined to one cerebral hemisphere. The method described herein provides a simple and noninvasive means to restrict visual input for studies of visual processing and learning in various rodent species.

Is the role of sleep in memory consolidation overrated?

Substantial empirical evidence suggests that sleep benefits the consolidation and reorganization of learned information. Consequently, the concept of "sleep-dependent memory consolidation" is now widely accepted by the scientific community, in addition to influencing public perceptions regarding the functions of sleep. There are, however, numerous studies that have presented findings inconsistent with the sleep-memory hypothesis. Here, we challenge the notion of "sleep-dependency" by summarizing evidence for effective memory consolidation independent of sleep. Plasticity mechanisms thought to mediate or facilitate consolidation during sleep (e.g., neuronal replay, reactivation, slow oscillations, neurochemical milieu) also operate during non-sleep states, particularly quiet wakefulness, thus allowing for the stabilization of new memories. We propose that it is not sleep per se, but the engagement of plasticity mechanisms, active during both sleep and (at least some) waking states, that constitutes the critical factor determining memory formation. Thus, rather than playing a "critical" role, sleep falls along a continuum of behavioral states that vary in their effectiveness to support memory consolidation at the neural and behavioral level.

NR2B-subunit dependent facilitation of long-term potentiation in primary visual cortex following visual discrimination training of adult rats.

Long-term potentiation (LTP) is an important mechanism thought to mediate changes in synaptic connectivity following various types of experience. We examined the effects of visual discrimination training on LTP in the mature, rodent thalamocortical visual system. Adult rats underwent visual discrimination training in a modified Morris Water Maze containing a Y-maze insert, requiring rats to associate visual cues with the location of a hidden escape platform placed in one of the two goal arms of the Y-maze insert. On the day following successful task acquisition (average of nine training days), rats were anesthetized (urethane), and LTP in the thalamocortical system was characterized. In task-naïve rats, theta-burst stimulation of the lateral geniculate nucleus resulted in modest (∼40%) potentiation of field postsynaptic potentials recorded in the primary visual cortex (V1). Rats trained on the visual discrimination task showed significantly greater levels of LTP (∼60%), an effect that was not seen in rats trained to swim in the maze without a predictive association between visual cues and platform location. An antagonist of the N-methyl-d-aspartate (NMDA) receptor NR2B subunit ([R-(R *,S *)]-α-(4-hydroxyphenyl)-ß-methyl-4-(phenylmethyl)-1-piperidinepropanol hydrochloride (Ro 25-6981); 2 mm, applied locally at the recording site in V1) reversed the training-induced LTP enhancement without affecting LTP in task-naïve rats. An antagonist of metabotropic glutamate receptors [(2S)-2-amino-2-[(1S,2S)-2-carboxycycloprop-1-yl]-3-(xanth-9-yl) propanoic acid (LY 341495); 2 mm] was ineffective in reversing the training-induced LTP facilitation. These data suggest that behavioral (visual) training can result in changes in plasticity exhibited by the mature, thalamocortical visual system that require activation of NMDA receptors containing the NR2B subunit.

Training-induced plasticity in the visual cortex of adult rats following visual discrimination learning.

Changes in synaptic efficacy, including long-term potentiation (LTP) and long-term depression (LTD), provide mechanisms for experience-induced plasticity and play a key role in learning processes. Some types of learning (e.g., motor learning, fear conditioning) result in LTP and/or LTD-like changes at synapses. Here, rats learned to discriminate two visual stimuli, P+ and P-, indicating the presence and absence, respectively, of a hidden escape platform in a Y-shaped water maze. Following task acquisition, trained rats showed larger amplitude of visually evoked potentials (VEPs) in V1 to both stimuli encountered during training relative to novel stimuli. Training also resulted in a facilitation of LTP induced by theta-burst stimulation (TBS) of thalamic afferents to V1 with no effect on depression induced by low-frequency stimulation (LFS). Visual VEP enhancement and increased LTP both required that visual stimuli carried some significance to the animal, as both effects were absent in control rats exposed to the same visual stimuli in the absence of pairing with platform location. Together, these experiments show that visual experience can result in a stimulus-selective response enhancement and an increase in the synaptic modification range of V1 synapses, providing a novel example of metaplasticity in circuits of the adult cortex.

Does Napping Enhance the Consolidation of Clinically Relevant Information? A Comparison of Individuals with Low and Elevated Depressive Symptoms.

PURPOSE: Sleep, both overnight and daytime naps, can facilitate the consolidation of declarative memories in healthy humans. However, it is unclear whether such beneficial effects of sleep occur in special populations, such as individuals with elevated neuropsychiatric symptoms, and if they apply to clinically relevant material that may have personal significance to those populations. METHODS: We examined memory retention over a 60-minute interval of wakefulness or nap opportunity in participants with low or elevated scores (≤13 and ≥21, respectively) on the Beck Depression Inventory-II (BDI-II). Memory for depression-related information was assessed by (a) free-recall of a video depicting a personal experience narrative of the impact of depression on cognition and workplace performance; and (b) a paired-associates task linking depression-related cognitive symptoms to appropriate coping strategies. RESULTS: The results showed no overall difference in recall between the nap and waking condition. However, across the full sample of participants, there were significant positive correlations between total sleep time and paired associates recall, and slow wave sleep (SWS) percentage and story free recall performance. Unexpectedly, participants with elevated BDI-II scores exhibited better free-recall performance compared to those with low scores. CONCLUSION: These results suggest that sleep, specifically SWS, may stabilize memories for clinically relevant information in populations with low and elevated depressive symptoms. The superior recall in participants with elevated-BDI scores may be related to the personal significance and stronger encoding of depression-related information. These observations raise the possibility that mnemonic deficits in depressed patients may be, at least in part, related to the type of information used to assess memory performance.

Low-frequency-induced synaptic potentiation: a paradigm shift in the field of memory-related plasticity mechanisms?

Long-term potentiation (LTP) and long-term depression (LTD) are two forms of synaptic plasticity thought to play functional roles in learning and memory processes. It is generally assumed that the direction of synaptic modifications (i.e., up- or down-regulation of synaptic strength) depends on the specific pattern of afferent inputs, with high frequency activity or stimulation effectively inducing LTP, while low-frequency patterns often elicit LTD. This dogma ("high frequency-LTP, low frequency-LTD") has recently been challenged by evidence demonstrating low frequency stimulation (LFS)-induced synaptic potentiation in the rodent hippocampus and amygdala. Extensive work in the past decades has focused on deciphering the mechanisms by which high frequency stimulation of afferent fiber systems results in LTP. With this review, we will compare and contrast the well-known synaptic and cellular mechanisms underlying classical, high-frequency-induced LTP to those mediating the more recently discovered phenomena of LFS-induced synaptic enhancement. In addition, we argue that LFS protocols provide a means to more accurately mimic some endogenous, oscillatory activity patterns present in hippocampal and extra-hippocampal (especially neocortical) circuits during periods of memory consolidation. Consequently, LFS-induced synaptic potentiation offers a novel and important avenue to investigate cellular and systems-level mechanisms mediating the encoding, consolidation, and transfer of information throughout multiple forebrain networks implicated in learning and memory processes. (c) 2009 Wiley-Liss, Inc.

Do rats (Rattus norvegicus) perceive biological motion?

It is unknown whether the rodent visual system can perceive biological motion, an ability present in primates, cats, and several bird species. Using a water-maze visual discrimination task, we find that rats can be trained to distinguish between left- and rightward motion of abstract point-light displays of walking humans. However, rats were unable to generalize to a novel point-light display (a walking cat), or to a display of a backward walking human, where overall body configuration and local, ballistic foot motion provide directly opposing cues regarding movement direction. Together, these experiments provide the first demonstration of the ability of rodents to extract motion direction cues from abstract, point-light displays. However, when isolated, neither the overall body configuration nor the local motion of the feet appears to provide sufficient information for rats to reliably extract movement direction in biological motion displays.

Alternating low frequency stimulation of medial septal and commissural fibers induces NMDA-dependent, long-lasting potentiation of hippocampal synapses in urethane-anesthetized rats.

Recent evidence indicates that some synapses exhibit long-lasting synaptic potentiation in response to low frequency (1 Hz) stimulation, similar to long-term potentiation (LTP) following high frequency induction protocols. Here, the authors characterize a form of long-lasting synaptic potentiation in the hippocampal CA1 area following alternating, single pulse stimulation of the medial septum (MS) and hippocampal CA3 commissural fibers (MS-H LTP). In urethane-anesthetized rats, alternating single pulse stimulation of the MS and CA3 (50 pulses each at 0.5 Hz, 1,000 ms interstimulus interval [ISI]) produced gradual increases of field excitatory postsynaptic potential (fEPSP) amplitude in CA1 ( approximately 123% of baseline), while MS or CA3 stimulation alone was ineffective. The fEPSP enhancement was long-lasting (>4h) and repeated episodes of alternating MS-CA3 stimulation tended to result in greater levels of potentiation than those elicited by a single episode. Surprisingly, ISIs of 500, 750, and 1,500 ms did not result in significant changes in fEPSP amplitude, while an ISI of 100 ms produced synaptic depression. MS-H LTP was resistant to systemic administration of nicotinic and muscarinic receptor antagonists (scopolamine, mecamylamine), but abolished by systemic MK-801 (0.5 mg/kg, i.p.) or local CA1 application of AP-V (10 mM), indicative of a critical role of hippocampal NMDA receptors in this effect. Paired-pulse facilitation experiments revealed a gradually developing, significant inverse correlation between fEPSP enhancement and decrease in paired-pulse facilitation ratio, suggesting a role of changes in presynaptic transmitter release. Together, these data demonstrate a novel form of long-lasting synaptic enhancement in CA1 neurons in response to low frequency activity in separate afferent systems, an activity that might mimic some aspects of natural discharge patterns during the acquisition or consolidation of memory processes in hippocampal circuits.

NR2B subunit-dependent long-term potentiation enhancement in the rat cortical auditory system in vivo following masking of patterned auditory input by white noise exposure during early postnatal life.

The composition of N-methyl-D-aspartate (NMDA) receptor subunits influences the degree of synaptic plasticity expressed during development and into adulthood. Here, we show that theta-burst stimulation of the medial geniculate nucleus reliably induced NMDA receptor-dependent long-term potentiation (LTP) of field postsynaptic potentials recorded in the primary auditory cortex (A1) of urethane-anesthetized rats. Furthermore, substantially greater levels of LTP were elicited in juvenile animals (30-37 days old; approximately 55% maximal potentiation) than in adult animals (approximately 30% potentiation). Masking patterned sound via continuous white noise exposure during early postnatal life (from postnatal day 5 to postnatal day 50-60) resulted in enhanced, juvenile-like levels of LTP (approximately 70% maximal potentiation) relative to age-matched controls reared in unaltered acoustic environments (approximately 30%). Rats reared in white noise and then placed in unaltered acoustic environments for 40-50 days showed levels of LTP comparable to those of adult controls, indicating that white noise rearing results in a form of developmental arrest that can be overcome by subsequent patterned sound exposure. We explored the mechanisms mediating white noise-induced plasticity enhancements by local NR2B subunit antagonist application in A1. NR2B subunit antagonists (Ro 25-6981 or ifenprodil) completely reversed white noise-induced LTP enhancement at concentrations that did not affect LTP in adult or age-matched controls. We conclude that white noise exposure during early postnatal life results in the maintenance of juvenile-like, higher levels of plasticity in A1, an effect that appears to be critically dependent on NR2B subunit activation.