Functionally Distinct Circuits Are Linked by Heterocellular Electrical Synapses in the Thalamic Reticular Nucleus.

The thalamic reticular nucleus (TRN) inhibits sensory thalamocortical relay neurons and is a key regulator of sensory attention as well as sleep and wake states. Recent developments have identified two distinct genetic subtypes of TRN neurons, calbindin-expressing (CB) and somatostatin-expressing (SOM) neurons. These subtypes differ in localization within the TRN, electrophysiological properties, and importantly, targeting of thalamocortical relay channels. CB neurons send inhibition to and receive excitation from first-order thalamic relay nuclei, while SOM neurons send inhibition to and receive excitation from higher-order thalamic areas. These differences create distinct channels of information flow. It is unknown whether TRN neurons form electrical synapses between SOM and CB neurons and consequently bridge first-order and higher-order thalamic channels. Here, we use GFP reporter mice to label and record from CB-expressing and SOM-expressing TRN neurons. We confirm that GFP expression properly differentiates TRN subtypes based on electrophysiological differences, and we identified electrical synapses between pairs of neurons with and without common GFP expression for both CB and SOM types. That is, electrical synapses link both within and across subtypes of neurons in the TRN, forming either homocellular or heterocellular synapses. Therefore, we conclude that electrical synapses within the TRN provide a substrate for functionally linking thalamocortical first-order and higher-order channels within the TRN.

GABABR Modulation of Electrical Synapses and Plasticity in the Thalamic Reticular Nucleus.

Two distinct types of neuronal activity result in long-term depression (LTD) of electrical synapses, with overlapping biochemical intracellular signaling pathways that link activity to synaptic strength, in electrically coupled neurons of the thalamic reticular nucleus (TRN). Because components of both signaling pathways can also be modulated by GABAB receptor activity, here we examined the impact of GABAB receptor activation on the two established inductors of LTD in electrical synapses. Recording from patched pairs of coupled rat neurons in vitro, we show that GABAB receptor inactivation itself induces a modest depression of electrical synapses and occludes LTD induction by either paired bursting or metabotropic glutamate receptor (mGluR) activation. GABAB activation also occludes LTD from either paired bursting or mGluR activation. Together, these results indicate that afferent sources of GABA, such as those from the forebrain or substantia nigra to the reticular nucleus, gate the induction of LTD from either neuronal activity or afferent glutamatergic receptor activation. These results add to a growing body of evidence that the regulation of thalamocortical transmission and sensory attention by TRN is modulated and controlled by other brain regions. Significance: We show that electrical synapse plasticity is gated by GABAB receptors in the thalamic reticular nucleus. This effect is a novel way for afferent GABAergic input from the basal ganglia to modulate thalamocortical relay and is a possible mediator of intra-TRN inhibitory effects.

Activity-dependent long-term potentiation of electrical synapses in the mammalian thalamus.

Activity-dependent changes of synapse strength have been extensively characterized at chemical synapses, but the relationship between physiological forms of activity and strength at electrical synapses remains poorly characterized and understood. For mammalian electrical synapses comprising hexamers of connexin36, physiological forms of neuronal activity in coupled pairs have thus far only been linked to long-term depression; activity that results in strengthening of electrical synapses has not yet been identified. Here, we performed dual whole-cell current-clamp recordings in acute slices of P11-P15 Sprague-Dawley rats of electrically coupled neurons of the thalamic reticular nucleus (TRN), a central brain area that regulates cortical input from and attention to the sensory surround. Using TTA-A2 to limit bursting, we show that tonic spiking in one neuron of a pair results in long-term potentiation of electrical synapses. We use experiments and computational modeling to show that the magnitude of plasticity expressed alters the functionality of the synapse. Potentiation is expressed asymmetrically, indicating that regulation of connectivity depends on the direction of use. Furthermore, calcium pharmacology and imaging indicate that potentiation depends on calcium flux. We thus propose a calcium-based activity rule for bidirectional plasticity of electrical synapse strength. Because electrical synapses dominate intra-TRN connectivity, these synapses and their activity-dependent modifications are key dynamic regulators of thalamic attention circuitry. More broadly, we speculate that bidirectional modifications of electrical synapses may be a widespread and powerful principle for ongoing, dynamic reorganization of neuronal circuitry across the brain.NEW & NOTEWORTHY This work reveals a physiologically relevant form of activity pairing in coupled neurons that results in long-term potentiation of mammalian electrical synapses. These findings, in combination with previous work, allow the authors to propose a bidirectional calcium-based rule for plasticity of electrical synapses, similar to those demonstrated for chemical synapses. These new insights inform the field on how electrical synapse plasticity may modify the neural circuits that incorporate them.

The Potential Role of Gap Junctional Plasticity in the Regulation of State.

Electrical synapses are the functional correlate of gap junctions and allow transmission of small molecules and electrical current between coupled neurons. Instead of static pores, electrical synapses are actually plastic, similar to chemical synapses. In the thalamocortical system, gap junctions couple inhibitory neurons that are similar in their biochemical profile, morphology, and electrophysiological properties. We postulate that electrical synaptic plasticity among inhibitory neurons directly interacts with the switching between different firing patterns in a state-dependent and type-dependent manner. In neuronal networks, electrical synapses may function as a modifiable resonance feedback system that enables stable oscillations. Furthermore, the plasticity of electrical synapses may play an important role in regulation of state, synchrony, and rhythmogenesis in the mammalian thalamocortical system, similar to chemical synaptic plasticity. Based on their plasticity, rich diversity, and specificity, electrical synapses are thus likely to participate in the control of consciousness and attention.

Electrical synapses and the development of inhibitory circuits in the thalamus.

KEY POINTS: The thalamus is a structure critical for information processing and transfer to the cortex. Thalamic reticular neurons are inhibitory cells interconnected by electrical synapses, most of which require the gap junction protein connexin36 (Cx36). We investigated whether electrical synapses play a role in the maturation of thalamic networks by studying neurons in mice with and without Cx36. When Cx36 was deleted, inhibitory synapses were more numerous, although both divergent inhibitory connectivity and dendritic complexity were reduced. Surprisingly, we observed non-Cx36-dependent electrical synapses with unusual biophysical properties interconnecting some reticular neurons in mice lacking Cx36. The results of the present study suggest an important role for Cx36-dependent electrical synapses in the development of thalamic circuits. ABSTRACT: Neurons within the mature thalamic reticular nucleus (TRN) powerfully inhibit ventrobasal (VB) thalamic relay neurons via GABAergic synapses. TRN neurons are also coupled to one another by electrical synapses that depend strongly on the gap junction protein connexin36 (Cx36). Electrical synapses in the TRN precede the postnatal development of TRN-to-VB inhibition. We investigated how the deletion of Cx36 affects the maturation of TRN and VB neurons, electrical coupling and GABAergic synapses by studying wild-type (WT) and Cx36 knockout (KO) mice. The incidence and strength of electrical coupling in TRN was sharply reduced, but not abolished, in KO mice. Surprisingly, electrical synapses between Cx36-KO neurons had faster voltage-dependent decay kinetics and conductance asymmetry (rectification) than did electrical synapses between WT neurons. The properties of TRN-mediated inhibition in VB also depended on the Cx36 genotype. Deletion of Cx36 increased the frequency and shifted the amplitude distributions of miniature IPSCs, whereas the paired-pulse ratio of evoked IPSCs was unaffected, suggesting that the absence of Cx36 led to an increase in GABAergic synaptic contacts. VB neurons from Cx36-KO mice also tended to have simpler dendritic trees and fewer divergent inputs from the TRN compared to WT cells. The findings obtained in the present study suggest that proper development of thalamic inhibitory circuitry, neuronal morphology, TRN cell function and electrical coupling requires Cx36. In the absence of Cx36, some TRN neurons express asymmetric electrical coupling mediated by other unidentified connexin subtypes.

Electrical coupling and innexin expression in the stomatogastric ganglion of the crab Cancer borealis.

Gap junctions are intercellular channels that allow for the movement of small molecules and ions between the cytoplasm of adjacent cells and form electrical synapses between neurons. In invertebrates, the gap junction proteins are coded for by the innexin family of genes. The stomatogastric ganglion (STG) in the crab Cancer borealis contains a small number of identified and electrically coupled neurons. We identified Innexin 1 (Inx1), Innexin 2 (Inx2), Innexin 3 (Inx3), Innexin 4 (Inx4), Innexin 5 (Inx5), and Innexin 6 (Inx6) members of the C. borealis innexin family. We also identified six members of the innexin family from the lobster Homarus americanus transcriptome. These innexins show significant sequence similarity to other arthropod innexins. Using in situ hybridization and reverse transcriptase-quantitative PCR (RT-qPCR), we determined that all the cells in the crab STG express multiple innexin genes. Electrophysiological recordings of coupling coefficients between identified pairs of pyloric dilator (PD) cells and PD-lateral posterior gastric (LPG) neurons show that the PD-PD electrical synapse is nonrectifying while the PD-LPG synapse is apparently strongly rectifying.

Synchronization dynamics induced on pairs of neurons under applied weak alternating magnetic fields.

Pairs of Helix aspersa neurons show an alternating magnetic field dependent frequency synchronization (AMFS) when exposed to a weak (amplitude B0 between 0.2 and 150 Gauss (G)) alternating magnetic field (AMF) of extremely low frequency (ELF, fM = 50 Hz). We have compared the AMFS patterns of discharge with: i) the synaptic activity promoted by glutamate and acetylcholine; ii) the activity induced by caffeine; iii) the bioelectric activity induced on neurons interconnected by electric synapses. AMFS activity reveals several specific features: i) a tight coincidence in time of the pattern and frequency, f, of discharge; ii) it is induced in the time interval of field application; iii) it is dependent on the intensity of the sinusoidal applied magnetic field; iv) elicited biphasic responses (excitation followed by inhibition) run in parallel for the pair of neurons; and v) some neuron pairs either spontaneously or AMF synchronized can be desynchronized under applied higher AMF. Our electron microscopy studies reveal gap-like junctions confirming our immunocytochemistry results about expression of connexin 26 (Cx26) in 4.7% of Helix neurons. AMF and carbenoxolone did not induce any significant effect on spontaneous synchronization through electric synapses.

Detection of a temporal error triggers reconsolidation of amygdala-dependent memories.

Updating memories is critical for adaptive behaviors, but the rules and mechanisms governing that process are still not well defined. During a limited time window, the reactivation of consolidated aversive memories triggers memory lability and induces a plasticity-dependent reconsolidation process in the lateral nucleus of amygdala (LA) [1-5]. However, whether new information is necessary for initiating reconsolidation is not known. Here we show that changing the temporal relationship between the conditioned stimulus (CS) and unconditioned stimulus (US) during reactivation is sufficient to trigger synaptic plasticity and reconsolidation of an aversive memory in the LA. These findings demonstrate that time is a core part of the CS-US association and that new information must be presented during reactivation in order to trigger LA-dependent reconsolidation processes. In sum, this study provides new basic knowledge about the precise rules governing memory reconsolidation of aversive memories that might be used to treat traumatic memories.

Música y cerebro (II): evidencias cerebrales del entrenamiento musical / Music and brain (II): evidence of musical training in the brain

La música es un estímulo multimodal muy potente que transmite información visual, auditiva y motora a nuestrocerebro, el cual cuenta con una red específica para su procesamiento, compuesta por regiones fronto-temporoparietales. Esta activación puede resultar muy provechosa en el tratamiento de diversos síndromes y enfermedades, ya sea rehabilitando o bien estimulando conexiones neuronales alteradas. Revisamos también las peculiaridades del cerebro del músico y vemos cómo el cerebro se adapta según las necesidades para mejorar su ejecución musical (AU)

Music is a very powerful multimodal stimulus that transmits visual, auditory and motor information to our brain, which in turn has a specific network for processing it, consisting in the frontotemporoparietal regions. This activation can be very beneficial in the treatment of several syndromes and diseases, either by rehabilitating or by stimulating altered neuronal connections. We also review the peculiarities of the musician’s brain and we look at how the brain adapts according to the needs that must be met in order to improve musical performance (AU)

Effects of electrical coupling among layer 4 inhibitory interneurons on contrast-invariant orientation tuning.

Simulations of orientation selectivity in visual cortex have shown that layer 4 complex cells lacking orientation tuning are ideal for providing global inhibition that scales with contrast in order to produce simple cells with contrast-invariant orientation tuning (Lauritzen and Miller in J Neurosci 23:10201-10213, 2003). Inhibitory cortical cells have been shown to be electrically coupled by gap junctions (Fukuda and Kosaka in J Neurosci 120:5-20, 2003). Such coupling promotes, among other effects, spike synchronization and coordination of postsynaptic IPSPs (Beierlein et al. in Nat Neurosci 3:904-910, 2000; Galarreta and Hestrin in Nat Rev Neurosci 2:425-433, 2001). Consequently, it was expected (Miller in Cereb Cortex 13:73-82, 2003) that electrical coupling would promote nonspecific functional responses consistent with the complex inhibitory cells seen in layer 4 which provide broad inhibition in response to stimuli of all orientations (Miller et al. in Curr Opin Neurobiol 11:488-497, 2001). This was tested using a mechanistic modeling approach. The orientation selectivity model of Lauritzen and Miller (J Neurosci 23:10201-10213, 2003) was reproduced with and without electrical coupling between complex inhibitory neurons. Although extensive coupling promotes uniform firing in complex cells, there were no detectable improvements in contrast-invariant orientation selectivity unless there were coincident changes in complex cell firing rates to offset the untuned excitatory component that grows with contrast. Thus, changes in firing rates alone (with or without coupling) could improve contrast-invariant orientation tuning of simple cells but not synchronization of complex inhibitory neurons alone.

Stability of electrical coupling despite massive developmental changes of intrinsic neuronal physiology.

Gap junctions mediate metabolic and electrical interactions between some cells of the CNS. For many types of neurons, gap junction-mediated electrical coupling is most prevalent during early development, then decreases sharply with maturation. However, neurons in the thalamic reticular nucleus (TRN), which exert powerful inhibitory control over thalamic relay cells, are electrically coupled in relatively mature animals. It is not known whether TRN cells or any neurons that are electrically coupled when mature are also coupled during early development. We used dual whole-cell recordings in mouse brain slices to study the postnatal development of electrical and chemical synapses that interconnect TRN neurons. Inhibitory chemical synapses were seen as early as postnatal day 4 but were infrequent at all ages, whereas TRN cells were extensively connected by electrical synapses from birth onward. Surprisingly, the functional strength of electrical coupling, assayed under steady-state conditions or during spiking, remained relatively constant as the brain matured despite dramatic concurrent changes of intrinsic membrane properties. Most notably, neuronal input resistances declined almost eightfold during the first two postnatal weeks, but there were offsetting increases in gap junctional conductances. This suggests that the size or number of gap junctions increase homeostatically to compensate for leakier nonjunctional membranes. Additionally, we found that the ability of electrical synapses to synchronize high frequency subthreshold signals improved as TRN cells matured. Our results demonstrate that certain central neurons may maintain or even increase their gap junctional communication as they mature.

NeuReal: an interactive simulation system for implementing artificial dendrites and large hybrid networks.

The dynamic clamp is a technique which allows the introduction of artificial conductances into living cells. Up to now, this technique has been mainly used to add small numbers of 'virtual' ion channels to real cells or to construct small hybrid neuronal circuits. In this paper we describe a prototype computer system, NeuReal, that extends the dynamic clamp technique to include (i) the attachment of artificial dendritic structures consisting of multiple compartments and (ii) the construction of large hybrid networks comprising several hundred biophysically realistic modelled neurons. NeuReal is a fully interactive system that runs on Windows XP, is written in a combination of C++ and assembler, and uses the Microsoft DirectX application programming interface (API) to achieve high-performance graphics. By using the sampling hardware-based representation of membrane potential at all stages of computation and by employing simple look-up tables, NeuReal can simulate over 1000 independent Hodgkin and Huxley type conductances in real-time on a modern personal computer (PC). In addition, whilst not being a hard real-time system, NeuReal still offers reliable performance and tolerable jitter levels up to an update rate of 50kHz. A key feature of NeuReal is that rather than being a simple dedicated dynamic clamp, it operates as a fast simulation system within which neurons can be specified as either real or simulated. We demonstrate the power of NeuReal with several example experiments and argue that it provides an effective tool for examining various aspects of neuronal function.