Learning-induced bidirectional enhancement of inhibitory synaptic metaplasticity.

Training rodents in a particularly difficult olfactory-discrimination (OD) task results in the acquisition of the ability to perform the task well, termed 'rule learning'. In addition to enhanced intrinsic excitability and synaptic excitation in piriform cortex pyramidal neurons, rule learning results in increased synaptic inhibition across the whole cortical network to the point where it precisely maintains the balance between inhibition and excitation. The mechanism underlying such precise inhibitory enhancement remains to be explored. Here, we use brain slices from transgenic mice (VGAT-ChR2-EYFP), enabling optogenetic stimulation of single GABAergic neurons and recordings of unitary synaptic events in pyramidal neurons. Quantal analysis revealed that learning-induced enhanced inhibition is mediated by increased quantal size of the evoked inhibitory events. Next, we examined the plasticity of synaptic inhibition induced by long-lasting, intrinsically evoked spike firing in post-synaptic neurons. Repetitive depolarizing current pulses from depolarized (-70 mV) or hyperpolarized (-90 mV) membrane potentials induced long-term depression (LTD) and long-term potentiation (LTP) of synaptic inhibition, respectively. We found a profound bidirectional increase in the ability to induce both LTD, mediated by L-type calcium channels, and LTP, mediated by R-type calcium channels after rule learning. Blocking the GABAB receptor reversed the effect of intrinsic stimulation at -90 mV from LTP to LTD. We suggest that learning greatly enhances the ability to modify the strength of synaptic inhibition of principal neurons in both directions. Such plasticity of synaptic plasticity allows fine-tuning of inhibition on each particular neuron, thereby stabilizing the network while maintaining the memory of the rule. KEY POINTS: Olfactory discrimination rule learning results in long-lasting enhancement of synaptic inhibition on piriform cortex pyramidal neurons. Quantal analysis of unitary inhibitory synaptic events, evoked by optogenetic minimal stimulation, revealed that enhanced synaptic inhibition is mediated by increased quantal size. Surprisingly, metaplasticity of synaptic inhibition, induced by intrinsically evoked repetitive spike firing, is increased bidirectionally. The susceptibility to both long-term depression (LTD) and long-term potentiation (LTP) of inhibition is enhanced after learning. LTD of synaptic inhibition is mediated by L-type calcium channels and LTP by R-type calcium channels. LTP is also dependent on activation of GABAB receptors. We suggest that learning-induced changes in the metaplasticity of synaptic inhibition enable the fine-tuning of inhibition on each particular neuron, thereby stabilizing the network while maintaining the memory of the rule.

The Firing of Theta State-Related Septal Cholinergic Neurons Disrupt Hippocampal Ripple Oscillations via Muscarinic Receptors.

The septo-hippocampal cholinergic system is critical for hippocampal learning and memory. However, a quantitative description of the in vivo firing patterns and physiological function of medial septal (MS) cholinergic neurons is still missing. In this study, we combined optogenetics with multichannel in vivo recording and recorded MS cholinergic neuron firings in freely behaving male mice for 5.5-72 h. We found that their firing activities were highly correlated with hippocampal theta states. MS cholinergic neurons were highly active during theta-dominant epochs, such as active exploration and rapid eye movement sleep, but almost silent during non-theta epochs, such as slow-wave sleep (SWS). Interestingly, optogenetic activation of these MS cholinergic neurons during SWS suppressed CA1 ripple oscillations. This suppression could be rescued by muscarinic M2 or M4 receptor antagonists. These results suggest the following important physiological function of MS cholinergic neurons: maintaining high hippocampal acetylcholine level by persistent firing during theta epochs, consequently suppressing ripples and allowing theta oscillations to dominate.SIGNIFICANCE STATEMENT The major source of acetylcholine in the hippocampus comes from the medial septum. Early experiments found that lesions to the MS result in the disappearance of hippocampal theta oscillation, which leads to speculation that the septo-hippocampal cholinergic projection contributing to theta oscillation. In this article, by long-term recording of MS cholinergic neurons, we found that they show a theta state-related firing pattern. However, optogenetically activating these neurons shows little effect on theta rhythm in the hippocampus. Instead, we found that activating MS cholinergic neurons during slow-wave sleep could suppress hippocampal ripple oscillations. This suppression is mediated by muscarinic M2 and M4 receptors.

The role of p21-activated kinase in maintaining the fear learning-induced modulation of excitation/inhibition ratio in lateral amygdala.

We study the relations between different learning paradigms and enduring changes in excitatory synaptic transmission. Here we show that auditory fear conditioning (AFC), but not olfactory fear conditioning (OFC) training, led to enduring enhancement in AMPA-mediated miniature EPSCs (mEPSCs). Moreover, olfactory unpaired training led to a stable significant reduction in excitatory synaptic transmission. However, olfactory discrimination learning (OD) did not modulate postsynaptic AMPA-mediated mEPSCs in LA. The p21-activated kinase (PAK) activity, previously shown to have a key role in maintaining persistent long-lasting enhancement in synaptic inhibition after OFC, has an opposing effect on excitatory synaptic transmission. PAK maintained the level of excitatory synaptic transmission in the amygdala in all experimental groups, except in neurons in the OFC trained rats. PAK also maintained excitatory synaptic transmission in all neurons of auditory fear conditioning and naïve training groups except in neurons of the auditory safety learning. Safety learning was previously shown in our study to enhance synaptic inhibition. We thus suggest that PAK maintains inhibitory synaptic transmission in a learning-dependent manner and on the other hand affects excitatory synaptic transmission only in groups where learning has not affected inhibitory transmission. Thus, PAK controls learning-induced changes in the excitation/inhibition balance.

Learning-induced enduring changes in inhibitory synaptic transmission in lateral amygdala are mediated by p21-activated kinase.

In this study we explored whether learning leads to enduring changes in inhibitory synaptic transmission in lateral amygdala (LA). We revealed that olfactory discrimination (OD) learning in rats led to a long-lasting increase in postsynaptic GABAA channel-mediated miniature inhibitory postsynaptic currents (mIPSCs) in LA. Olfactory fear conditioning, but not auditory fear conditioning, also led to enduring enhancement in GABAA-mediated mIPSCs. Auditory fear conditioning, but not olfactory fear conditioning or OD learning, induced an enduring reduction in the frequency but not the current of mIPSC events. We found that p21-activated kinase (PAK) activity is needed to maintain OD and olfactory fear conditioning learning-induced enduring enhancement of mIPSCs. Further analysis revealed that OD led to an increase in GABAA channel conductance whereas olfactory fear conditioning increased the number of GABAA channels. These alterations in GABAA channels conductance and level are controlled by PAK activity. Our study shows that the learning-induced increase in postsynaptic inhibitory transmission in LA is specific to the sensory modality. However, the mechanism that mediates the increase in inhibitory transmission, namely the increase in the conductance or in the level of GABAA channel, is learning specific.NEW & NOTEWORTHY Here we studied whether learning leads to long-lasting alterations in inhibitory synaptic transmission in lateral amygdala (LA). We revealed that learning led to enduring changes in inhibitory synaptic transmission in LA that are affected by the sensory modality (auditory or olfaction) used during learning. However, the mechanism that mediated the changes in inhibitory transmission (alterations in GABAA channel level or conductance) depended on the type of learning. These long-lasting alterations are maintained by p21-activated kinase.

Tune it in: mechanisms and computational significance of neuron-autonomous plasticity.

The activity of a neural network is a result of synaptic signals that convey the communication between neurons and neuron-based intrinsic currents that determine the neuron's input-output transfer function. Ample studies have demonstrated that cell-based excitability, and in particular intrinsic excitability, is modulated by learning and that these modifications play a key role in learning-related behavioral changes. The field of cell-based plasticity is largely growing, and it entails numerous experimental findings that demonstrate a large diversity of currents that are affected by learning. The diverse effect of learning on the neuron's excitability emphasizes the need for a framework under which cell-based plasticity can be categorized to enable the assessment of the computational roles of the intrinsic modifications. We divide the domain of cell-based plasticity into three main categories, where the first category entails the currents that mediate the passive properties and single-spike generation, the second category entails the currents that mediate spike frequency adaptation, and the third category entails a novel learning-induced mechanism where all excitatory and inhibitory synapses double their strength. Curiously, this elementary division enables a natural categorization of the computational roles of these learning-induced plasticities. The computational roles are diverse and include modification of the neuronal mode of action, such as bursting, prolonged, and fast responsive; attention-like effect where the signal detection is improved; transfer of the network into an active state; biasing the competition for memory allocation; and transforming an environmental cue into a dominant cue and enabling a quicker formation of new memories.

Learning-induced modulation of the effect of neuroglial transmission on synaptic plasticity.

Training rats in a complex olfactory discrimination task results in acquisition of "rule learning" (learning how to learn), a term describing the capability to perform the task superbly. Such rule learning results in strengthening of both excitatory and inhibitory synaptic connections between neurons in the piriform cortex. Moreover, intrinsic excitability is also enhanced throughout the pyramidal neuron population. Surprisingly, the cortical network retains its stability under these long-term modifications. In particular, the susceptibility for long-term potentiation (LTP) induction, while decreased for a short time window, returns to almost its pretraining value, although significant strengthening of AMPA receptor-mediated glutamatergic transmission remains. Such network balance is essential for maintaining the single-cell modifications that underlie long-term memory while preventing hyperexcitability that would result in runaway synaptic activity. However, the mechanisms underlying the long-term maintenance of such balance have yet to be described. In this study, we explored the role of astrocyte-mediated gliotransmission in long-term maintenance of learning-induced modifications in susceptibility for LTP induction and control of the strength of synaptic inhibition. We show that blocking connexin 43 hemichannels, which form gap junctions between astrocytes, decreases significantly the ability to induce LTP by stimulating the excitatory connections between piriform cortex pyramidal neurons after learning only. In parallel, spontaneous miniature inhibitory postsynaptic current amplitude is reduced in neurons from trained rats only, to the level of prelearning. Thus gliotransmission has a key role in maintaining learning-induced cortical stability by a wide-ranged control on synaptic transmission and plasticity. NEW & NOTEWORTHY We explore the role of astrocyte-mediated gliotransmission in maintenance of olfactory discrimination learning-induced modifications. We show that blocking gap junctions between astrocytes decreases significantly the ability to induce long-term potentiation in the piriform cortex after learning only. In parallel, synaptic inhibition is reduced in neurons from trained rats only, to the level of prelearning. Thus gliotransmission has a key role in maintaining learning-induced cortical stability by a wide-ranged control on synaptic transmission and plasticity.

Learning-induced modulation of the effect of endocannabinoids on inhibitory synaptic transmission.

are key modulators that regulate central brain functions and behaviors, including learning and memory. At the cellular and molecular levels, endocannabinoids are potent modulators of excitatory and inhibitory synaptic function. Most effects of cannabinoids are thought to be mediated via G protein-coupled cannabinoid receptors. In particular, cannabinoids released from postsynaptic neurons are suggested to act as retrograde messengers, activating presynaptic type-1 cannabinoid receptors (CB1Rs), thereby inducing suppression of synaptic release. Another central mechanism of cannabinoid-induced action requires activation of astroglial CB1Rs. CB1Rs are also implicated in self-modulation of cortical neurons. Rats that are trained in a particularly difficult olfactory-discrimination task show a dramatic increased ability to acquire memories of new odors. The memory of the acquired high-skill acquisition, termed "rule learning" or "learning set," lasts for many months. Using this behavioral paradigm, we show a novel function of action for CB1Rs, supporting long-term memory by maintaining persistent enhancement of inhibitory synaptic transmission. Long-lasting enhancement of inhibitory synaptic transmission is blocked by a CB1R inverse agonist. This effect is mediated by a novel purely postsynaptic mechanism, obtained by enhancing the single GABAA channel conductance that is PKA dependent. The significant role that CB1R has in maintaining learning-induced long-term strengthening of synaptic inhibition suggests that endocannabinoids have a key role in maintaining long-term memory by enhancing synaptic inhibition. NEW & NOTEWORTHY In this study we show a novel function and mechanism of action for cannabinoids in neurons, mediated by activation of type-1 cannabinoid receptors, supporting long-term memory by maintaining persistent enhancement of inhibitory synaptic transmission on excitatory neurons. This effect is mediated by a novel purely postsynaptic mechanism, obtained by enhancing the single GABAA channel conductance that is PKA dependent. Thus we report for the first time that endocannabinoids have a key role maintaining learning-induced synaptic modification.

A non-synaptic mechanism of complex learning: Modulation of intrinsic neuronal excitability.

Training rats in a particularly difficult olfactory discrimination task initiates a period of accelerated learning of other odors, manifested as a dramatic increase in the rats' capacity to acquire memories for new odors once they have learned the first discrimination task, implying that rule learning has taken place. At the cellular level, pyramidal neurons in the piriform cortex, hippocampus and bsolateral amygdala of olfactory-discrimination trained rats show enhanced intrinsic neuronal excitability that lasts for several days after rule learning. Such enhanced intrinsic excitability is mediated by long-term reduction in the post-burst after-hyperpolarization (AHP) which is generated by repetitive spike firing, and is maintained by persistent activation of key second messenger systems. Much like late-LTP, the induction of long-term modulation of intrinsic excitability is protein synthesis dependent. Learning-induced modulation of intrinsic excitability can be bi-directional, pending of the valance of the outcome of the learned task. In this review we describe the physiological and molecular mechanisms underlying the rule learning-induced long-term enhancement in neuronal excitability and discuss the functional significance of such a wide spread modulation of the neurons' ability to sustain repetitive spike generation.

Real Time Multiplicative Memory Amplification Mediated by Whole-Cell Scaling of Synaptic Response in Key Neurons.

Intense spiking response of a memory-pattern is believed to play a crucial role both in normal learning and pathology, where it can create biased behavior. We recently proposed a novel model for memory amplification where the simultaneous two-fold increase of all excitatory (AMPAR-mediated) and inhibitory (GABAAR-mediated) synapses in a sub-group of cells that constitutes a memory-pattern selectively amplifies this memory. Here we confirm the cellular basis of this model by validating its major predictions in four sets of experiments, and demonstrate its induction via a whole-cell transduction mechanism. Subsequently, using theory and simulations, we show that this whole-cell two-fold increase of all inhibitory and excitatory synapses functions as an instantaneous and multiplicative amplifier of the neurons' spiking. The amplification mechanism acts through multiplication of the net synaptic current, where it scales both the average and the standard deviation of the current. In the excitation-inhibition balance regime, this scaling creates a linear multiplicative amplifier of the cell's spiking response. Moreover, the direct scaling of the synaptic input enables the amplification of the spiking response to be synchronized with rapid changes in synaptic input, and to be independent of previous spiking activity. These traits enable instantaneous real-time amplification during brief elevations of excitatory synaptic input. Furthermore, the multiplicative nature of the amplifier ensures that the net effect of the amplification is large mainly when the synaptic input is mostly excitatory. When induced on all cells that comprise a memory-pattern, these whole-cell modifications enable a substantial instantaneous amplification of the memory-pattern when the memory is activated. The amplification mechanism is induced by CaMKII dependent phosphorylation that doubles the conductance of all GABAA and AMPA receptors in a subset of neurons. This whole-cell transduction mechanism enables both long-term induction of memory amplification when necessary and extinction when not further required.

Theta Rhythmic Clock-Like Activity of Single Units in the Mouse Hippocampus.

Theta rhythmic clock-like activity was observed in a small group of hippocampal CA1 neurons in freely behaving mice. These neurons were only persistently activated during theta states of waking exploration and rapid eye movement sleep, but were almost silent during the non-theta state of slow-wave sleep. Interestingly, these cells displayed a theta clock-like simple-spike firing pattern, and were capable of firing one spike per theta cycle during theta states. This is the first report of a unique class of hippocampal neurons with a clock-like firing pattern at the theta rhythm. We speculate that these cells may act as a temporal reference to participate in the theta-related temporal coding in the hippocampus. SIGNIFICANCE STATEMENT: Theta oscillations, as the predominant rhythms in the hippocampus during waking exploration and rapid eye movement sleep, may be critical for temporal coding/decoding of neuronal information, and theta-phase precession in hippocampal place cells is one of the best demonstrations of such temporal coding. Here, we show that a unique small class of hippocampal CA1 neurons fired with a theta rhythmic clock-like firing pattern during theta states. These firing characteristics support the notion that these neurons may play a critical role in theta-related temporal coding in the hippocampus.

Persistent CaMKII activation mediates learning-induced long-lasting enhancement of synaptic inhibition.

Training rats in a particularly difficult olfactory-discrimination task results in acquisition of high skill to perform the task superbly, termed "rule learning" or "learning set." Such complex learning results in enhanced intrinsic neuronal excitability of piriform cortex pyramidal neurons, and in their excitatory synaptic interconnections. These changes, while subserving memory maintenance, must be counterbalanced by modifications that prevent overspreading of activity and uncontrolled synaptic strengthening. Indeed, we have previously shown that the average amplitude of GABAA-mediated miniature IPSCs (mIPSCs) in these neurons is enhanced for several days after learning, an enhancement mediated via a postsynaptic mechanism. To unravel the molecular mechanism of this long-term inhibition enhancement, we tested the role of key second-messenger systems in maintaining such long-lasting modulation. The calcium/calmodulin-dependent kinase II (CaMKII) blocker, KN93, significantly reduced the average mIPSC amplitude in neurons from trained rats only to the average pretraining level. A similar effect was obtained by the CaMKII peptide inhibitor, tatCN21. Such reduction resulted from decreased single-channel conductance and not in the number of activated channels. The PKC inhibitor, GF109203X, reduced the average mIPSC amplitude in neurons from naive, pseudo-trained, and trained animals, and the difference between the trained and control groups remained. Such reduction resulted from a decrease in the number of activated channels. The PKA inhibitor H89 dihydrochloride did not affect the average mIPSC amplitude in neurons from any of the three groups. We conclude that learning-induced enhancement of GABAA-mediated synaptic inhibition is maintained by persistent CaMKII activation.

Calcium/calmodulin-dependent kinase II activity is required for maintaining learning-induced enhancement of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor-mediated synaptic excitation.

Learning leads to changes in α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-mediated synaptic excitation. The mechanisms for maintaining such alterations needed for memory persistence remain to be clarified. Here, we report a novel molecular mechanism for maintaining learning-induced AMPAR-mediated enhancement of synaptic excitation. We show that training rats in a complex olfactory discrimination task, such that requires rule learning, leads to the enhancement of averaged amplitude of AMPAR-mediated miniature excitatory post-synaptic currents (mEPSCs) in piriform cortex pyramidal neurons for days after learning. Inhibiting calcium/calmodulin-dependent kinase II (CaMKII) using KN93 or tatCN21 days after learning, reduced the averaged mEPSC amplitude in neurons in piriform cortex of trained rats to the level where they are not significantly different from mEPSC of control animals. CaMKII inhibition leads to a decrease in single channel conductance and not to changes in the number of synaptic-activated channels. We conclude that the maintenance of learning-induced enhancement of AMPAR-mediated synaptic excitation requires the activity of calcium/calmodulin-dependent kinase II. We show that training rats in a complex olfactory discrimination task leads to the enhancement of averaged amplitude of AMPA receptor-mediated miniature excitatory post-synaptic currents (mEPSCs) in piriform cortex pyramidal neurons for days after learning. Inhibiting calcium/calmodulin-dependent kinase II (CaMKII) using KN93 or tatCN21 days after learning, reduced the averaged mEPSC amplitude in neurons in piriform cortex of trained rats to the level where they are not significantly different from mEPSC of control animals. CaMKII inhibition leads to a decrease in AMPAR single channel conductance. We conclude that the maintenance of learning-induced enhancement of AMPAR-mediated synaptic excitation requires the activity of CaMKII.

Differential modifications of synaptic weights during odor rule learning: dynamics of interaction between the piriform cortex with lower and higher brain areas.

Learning of a complex olfactory discrimination (OD) task results in acquisition of rule learning after prolonged training. Previously, we demonstrated enhanced synaptic connectivity between the piriform cortex (PC) and its ascending and descending inputs from the olfactory bulb (OB) and orbitofrontal cortex (OFC) following OD rule learning. Here, using recordings of evoked field postsynaptic potentials in behaving animals, we examined the dynamics by which these synaptic pathways are modified during rule acquisition. We show profound differences in synaptic connectivity modulation between the 2 input sources. During rule acquisition, the ascending synaptic connectivity from the OB to the anterior and posterior PC is simultaneously enhanced. Furthermore, post-training stimulation of the OB enhanced learning rate dramatically. In sharp contrast, the synaptic input in the descending pathway from the OFC was significantly reduced until training completion. Once rule learning was established, the strength of synaptic connectivity in the 2 pathways resumed its pretraining values. We suggest that acquisition of olfactory rule learning requires a transient enhancement of ascending inputs to the PC, synchronized with a parallel decrease in the descending inputs. This combined short-lived modulation enables the PC network to reorganize in a manner that enables it to first acquire and then maintain the rule.

Learning-induced bidirectional plasticity of intrinsic neuronal excitability reflects the valence of the outcome.

Long-term memory is supported not only by modulation of synaptic strength, but also by modifications in intrinsic neuronal properties. Learning-induced enhancement of neuronal excitability has been shown in the hippocampus and the piriform cortex, where it lasts for days and is involved in maintaining the learned skills. The basolateral amygdala (BLA) is suggested to encode positive and negative significance of information, thus forming a unique experimental setting to monitor bidirectional changes as a function of the valence change. In rodents, olfaction is a major modality that guides goal-directed behavior. Here, we show that intrinsic neuronal excitability in BLA pyramidal neurons is differentially modified by positive and negative olfactory learning and explore the cellular mechanisms of such bidirectional intrinsic neuronal plasticity. Learning of complex olfactory-discrimination task, in which success was rewarded with drinking water, resulted with enhanced intrinsic excitability. Such enhancement is mediated by reduction in the slow potassium current. In contrast, olfactory fear conditioning, in which the animal learned to associate the odor with an electric shock, resulted in decreased intrinsic excitability, mediated by activation of the µ-opioid-sensitive potassium current. We suggest that positive and negative changes in BLA excitability contribute to the encoding of opposite odor-value behaviors.

Learning-induced modulation of the GABAB-mediated inhibitory synaptic transmission: mechanisms and functional significance.

Complex olfactory-discrimination (OD) learning results in a series of intrinsic and excitatory synaptic modifications in piriform cortex pyramidal neurons that enhance the circuit excitability. Such overexcitation must be balanced to prevent runway activity while maintaining the efficient ability to store memories. We showed previously that OD learning is accompanied by enhancement of the GABAA-mediated inhibition. Here we show that GABAB-mediated inhibition is also enhanced after learning and study the mechanism underlying such enhancement and explore its functional role. We show that presynaptic, GABAB-mediated synaptic inhibition is enhanced after learning. In contrast, the population-average postsynaptic GABAB-mediated synaptic inhibition is unchanged, but its standard deviation is enhanced. Learning-induced reduction in paired pulse facilitation in the glutamatergic synapses interconnecting pyramidal neurons was abolished by application of the GABAB antagonist CGP55845 but not by blocking G protein-gated inwardly rectifying potassium channels only, indicating enhanced suppression of excitatory synaptic release via presynaptic GABAB-receptor activation. In addition, the correlation between the strengths of the early (GABAA-mediated) and late (GABAB-mediated) synaptic inhibition was much stronger for each particular neuron after learning. Consequently, GABAB-mediated inhibition was also more efficient in controlling epileptic-like activity induced by blocking GABAA receptors. We suggest that complex OD learning is accompanied by enhancement of the GABAB-mediated inhibition that enables the cortical network to store memories, while preventing uncontrolled activity.

Reversing Aging: Decline in Complex Olfactory Learning Can be Rectified by Restoring Intrinsic Plasticity of Hippocampal CA1 Pyramidal Neurons.

The acquisition of complex rules requires modifications in intrinsic plasticity of excitatory neurons within relevant brain areas. Olfactory discrimination (OD) rule learning occludes slow calcium-dependent potassium current (sIAHP ) in piriform cortex (PC) pyramidal neurons, which increases their intrinsic neuronal excitability. Similar learning-induced sIAHP changes are demonstrated in hippocampal CA1. The shutdown of sIAHP is mediated by the metabotropic activation of the kainate subtype glutamatergic receptor, GluK2. Here, the duration of training required for OD rule learning increased significantly as the mice matured and aged is first shown, which appears earlier in 5xFAD mice. At the cellular biophysical level, aging is accompanied by reduction in the post-burst AHP in these neurons, while neuronal excitability remains stable. This is in contrast to aging CA1 neurons that exhibit enhanced post-burst AHPs in previous reports. Kainate reduces post-burst AHP in adults, but not in aged PC neurons, whereas it reduces post-burst AHPs in hippocampal CA1 pyramidal neurons of both young and aged mice. Overexpression of GluK2 in CA1 neurons restores OD learning capabilities in aged wild-type and 5xFAD mice, to a level comparable to young adults. Activation of GluK2 receptors in selectively vulnerable neurons can prevent aging-related cognitive decline is suggested.

Modulation of social investigation by anterior hypothalamic nucleus rhythmic neural activity.

Social interactions involve both approach and avoidance toward specific individuals. Currently, the brain regions subserving these behaviors are not fully recognized. The anterior hypothalamic nucleus (AHN) is a poorly defined brain area, and recent studies have yielded contradicting conclusions regarding its behavioral role. Here we explored the role of AHN neuronal activity in regulating approach and avoidance actions during social interactions. Using electrophysiological recordings from behaving mice, we revealed that theta rhythmicity in the AHN is enhanced during affiliative interactions, but decreases during aversive ones. Moreover, the spiking activity of AHN neurons increased during the investigation of social stimuli, as compared to objects, and was modulated by theta rhythmicity. Finally, AHN optogenetic stimulation during social interactions augmented the approach toward stimuli associated with the stimulation. These results suggest the role for AHN neural activity in regulating approach behavior during social interactions, and for theta rhythmicity in mediating the valence of social stimuli.

Mechanisms underlying rule learning-induced enhancement of excitatory and inhibitory synaptic transmission.

Training rats to perform rapidly and efficiently in an olfactory discrimination task results in robust enhancement of excitatory and inhibitory synaptic connectivity in the rat piriform cortex, which is maintained for days after training. To explore the mechanisms by which such synaptic enhancement occurs, we recorded spontaneous miniature excitatory and inhibitory synaptic events in identified piriform cortex neurons from odor-trained, pseudo-trained, and naive rats. We show that olfactory discrimination learning induces profound enhancement in the averaged amplitude of AMPA receptor-mediated miniature synaptic events in piriform cortex pyramidal neurons. Such physiological modifications are apparent at least 4 days after learning completion and outlast learning-induced modifications in the number of spines on these neurons. Also, the averaged amplitude of GABA(A) receptor-mediated miniature inhibitory synaptic events was significantly enhanced following odor discrimination training. For both excitatory and inhibitory transmission, an increase in miniature postsynaptic current amplitude was evident in most of the recorded neurons; however, some neurons showed an exceptionally great increase in the amplitude of miniature events. For both excitatory and inhibitory transmission, the frequency of spontaneous synaptic events was not modified after learning. These results suggest that olfactory discrimination learning-induced enhancement of synaptic transmission in cortical neurons is mediated by postsynaptic modulation of AMPA receptor-dependent currents and balanced by long-lasting modulation of postsynaptic GABA(A) receptor-mediated currents.

Olfactory learning-induced enhancement of the predisposition for LTP induction.

Learning of a particularly difficult olfactory-discrimination (OD) task results in acquisition of rule learning. This enhancement in learning capability is accompanied by the long-term enhancement of synaptic connectivity between piriform cortex pyramidal neurons. In this study we examined whether olfactory rule learning would modify the predisposition to induce long-term potentiation (LTP) in the pathway projecting from the piriform cortex to the olfactory bulb. We report that OD learning was associated with enhancement in the predisposition to induce LTP. This learning-related effect may be affected by process generation of new granule cells located in the olfactory bulb.

Olfactory rule learning-induced enhancement in intrinsic neuronal excitability is maintained by shutdown of the cholinergic M-current.

Training rats in a particularly difficult olfactory discrimination task initiates a period of accelerated learning, manifested as a dramatic increase in the rats' capacity to discriminate between pairs of odors once they have learned the discrimination task, implying that rule learning has taken place. At the cellular biophysical level, rule learning is maintained by reduction in the conductance of the slow current (sIAHP) simultaneously in most piriform cortex layer II pyramidal neurons. Such sIAHP reduction is expressed in attenuation of the post-burst afterhyperpolarization (AHP) potential and thus in enhanced repetitive action potential firing. Previous studies have shown that a causal relationship exists between long-lasting post-burst AHP reduction and rule learning. A specific channel through which the sIAHP flows has not been identified. The sIAHP in pyramidal cells is critically dependent on membrane phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P(2)]. PtdIns(4,5)P(2) regulates the calcium sensitivity of the sIAHP by acting downstream from the rise in intracellular calcium. These findings led to the interesting hypothesis that PtdIns(4,5)P(2) activates a variety of potassium channels. Thus, the sIAHP would not represent a unitary ionic current but the embodiment of a generalized potassium channel gating mechanism. We thus hypothesized that the learning-induced increase in intrinsic excitability is mediated by reduced conductance of one or more of the currents that contribute to the sIAHP. Here we first show, using current-clamp recordings, that the post-burst AHP in piriform cortex pyramidal neurons is also mediated by the Ih, and the contribution of this current to the post-burst AHP is also affected by learning. We also show, using whole-cell patch-clamp recordings, that the sIAHP in neurons from trained rats is not sensitive to blocking membrane phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P(2)], and to the blocking of the current mediated by the cholinergic muscarinic acetylcholine receptor (M-current). Further current-clamp recordings also show that blocking PtdIns(4,5)P(2) synthesis and application of a specific IKCa blocker have no effect on the post-burst AHP in neurons from trained as well as control rats. Taken together with results from our previous studies, these data suggest that rule learning-induced long-lasting enhancement in intrinsic neuronal excitability results from reduced conductance of the M-current and thus the slow potassium currents, which control repetitive spike firing.