Conditioned approach behavior of SHR and SD rats during Pavlovian conditioning

Individual differences in reward-related learning are relevant to many behavioral disorders. Sensory cues that predict reward can become incentive stimuli that adaptively support behavior, or alternatively, cause maladaptive behaviors. The spontaneously hypertensive rat (SHR) expresses a genetically determined elevated sensitivity to delay of reward, and has been extensively studied as a behavioral model for attention deficit hyperactivity disorder (ADHD). We investigated reward-related learning in the SHR, comparing them to Sprague-Dawley (SD) rats as a reference strain. A standard Pavlovian conditioned approach task was used, in which a lever cue was followed by reward. Lever presses could occur while the lever was extended, but had no effect on reward delivery. The behavior of both the SHRs and the SD rats showed that they learnt that the lever cue predicted reward. However, the pattern of behavior differed between the strains. During lever cue presentation, SD rats pressed the lever more often and made fewer magazine entries than SHRs. When lever contacts that did not result in lever presses were analyzed, there was no significant difference between SHRs and SDs. These results suggest that the SHRs attributed less incentive value to the conditioned stimulus than the SD rats. During the presentation of the conditioned cue, cue directed responses are called sign tracking responses, whereas responses directed towards the food magazine are called goal tracking responses. Analysis of behavior using a standard Pavlovian conditioned approach index to quantify sign and goal tracking tendencies showed that both strains had a tendency towards goal tracking in this task. However, the SHRs showed a significantly greater goal tracking tendency than the SD rats. Taken together, these findings suggest that attribution of incentive value to reward predicting cues is attenuated in SHRs, which might explain their elevated sensitivity to delay of reward.journal articl

Timing is not Everything: Neuromodulation Opens the STDP Gate

Spike timing dependent plasticity (STDP) is a temporally specific extension of Hebbian associative plasticity that has tied together the timing of presynaptic inputs relative to the postsynaptic single spike. However, it is difficult to translate this mechanism to in vivo conditions where there is an abundance of presynaptic activity constantly impinging upon the dendritic tree as well as ongoing postsynaptic spiking activity that backpropagates along the dendrite. Theoretical studies have proposed that, in addition to this pre- and postsynaptic activity, a “third factor” would enable the association of specific inputs to specific outputs. Experimentally, the picture that is beginning to emerge, is that in addition to the precise timing of pre- and postsynaptic spikes, this third factor involves neuromodulators that have a distinctive influence on STDP rules. Specifically, neuromodulatory systems can influence STDP rules by acting via dopaminergic, noradrenergic, muscarinic, and nicotinic receptors. Neuromodulator actions can enable STDP induction or – by increasing or decreasing the threshold – can change the conditions for plasticity induction. Because some of the neuromodulators are also involved in reward, a link between STDP and reward-mediated learning is emerging. However, many outstanding questions concerning the relationship between neuromodulatory systems and STDP rules remain, that once solved, will help make the crucial link from timing-based synaptic plasticity rules to behaviorally based learning

Timing is not Everything: Neuromodulation Opens the STDP Gate

Spike timing dependent plasticity (STDP) is a temporally specific extension of Hebbian associative plasticity that has tied together the timing of presynaptic inputs relative to the postsynaptic single spike. However, it is difficult to translate this mechanism to in vivo conditions where there is an abundance of presynaptic activity constantly impinging upon the dendritic tree as well as ongoing postsynaptic spiking activity that backpropagates along the dendrite. Theoretical studies have proposed that, in addition to this pre- and postsynaptic activity, a “third factor” would enable the association of specific inputs to specific outputs. Experimentally, the picture that is beginning to emerge, is that in addition to the precise timing of pre- and postsynaptic spikes, this third factor involves neuromodulators that have a distinctive influence on STDP rules. Specifically, neuromodulatory systems can influence STDP rules by acting via dopaminergic, noradrenergic, muscarinic, and nicotinic receptors. Neuromodulator actions can enable STDP induction or – by increasing or decreasing the threshold – can change the conditions for plasticity induction. Because some of the neuromodulators are also involved in reward, a link between STDP and reward-mediated learning is emerging. However, many outstanding questions concerning the relationship between neuromodulatory systems and STDP rules remain, that once solved, will help make the crucial link from timing-based synaptic plasticity rules to behaviorally based learning

Synchronization of Midbrain Dopaminergic Neurons Is Enhanced by Rewarding Events

SummaryThe basal ganglia network is divided into two functionally related subsystems: the neuromodulators and the main axis. It is assumed that neuromodulators adjust cortico-striatal coupling. This adjustment might depend on the response properties and temporal interactions between neuromodulators. We studied functional interactions between simultaneously recorded pairs of neurons in the basal ganglia while monkeys performed a classical conditioning task that included rewarding, neutral, and aversive events. Neurons that belong to a single neuromodulator group exhibited similar average responses, whereas main axis neurons responded in a highly diverse manner. Dopaminergic neuromodulators transiently increased trial-to-trial (noise) correlation following rewarding but not aversive events, whereas cholinergic neurons of the striatum decreased their trial-to-trial correlation. These changes in functional connectivity occurred at different epochs of the trial. Thus, the coding scheme of neuromodulators (but not main axis neurons) can be viewed as a single-dimensional code that is further enriched by dynamic neuronal interactions

Three-Dimensional Spatial Analyses of Cholinergic Neuronal Distributions Across The Mouse Septum, Nucleus Basalis, Globus Pallidus, Nucleus Accumbens, and Caudate-Putamen

Neuronal networks are regulated by three-dimensional spatial and structural properties. Despite robust evidence of functional implications in the modulation of cognition, little is known about the three-dimensional internal organization of cholinergic networks in the forebrain. Cholinergic networks in the forebrain primarily occur in subcortical nuclei, specifically the septum, nucleus basalis, globus pallidus, nucleus accumbens, and the caudate-putamen. Therefore, the present investigation analyzed the three-dimensional spatial organization of 14,000 cholinergic neurons that expressed choline acetyltransferase (ChAT) in these subcortical nuclei of the mouse forebrain. Point process theory and graph signal processing techniques identified three topological principles of organization. First, cholinergic interneuronal distance is not uniform across brain regions. Specifically, in the septum, globus pallidus, nucleus accumbens, and the caudate-putamen, the cholinergic neurons were clustered compared with a uniform random distribution. In contrast, in the nucleus basalis, the cholinergic neurons had a spatial distribution of greater regularity than a uniform random distribution. Second, a quarter of the caudate-putamen is composed of axonal bundles, yet the spatial distribution of cholinergic neurons remained clustered when axonal bundles were accounted for. However, comparison with an inhomogeneous Poisson distribution showed that the nucleus basalis and caudate-putamen findings could be explained by density gradients in those structures. Third, the number of cholinergic neurons varies as a function of the volume of a specific brain region but cell body volume is constant across regions. The results of the present investigation provide topographic descriptions of cholinergic somata distribution and axonal conduits, and demonstrate spatial differences in cognitive control networks. The study provides a comprehensive digital database of the total population of ChAT-positive neurons in the reported structures, with the x,y,z coordinates of each neuron at micrometer resolution. This information is important for future digital cellular atlases and computational models of the forebrain cholinergic system enabling models based on actual spatial geometry

Dynamic control of neurochemical release with ultrasonically-sensitive nanoshell-tethered liposomes

The unique surface plasmon resonance of hollow gold nanoshells can be used to achieve drug release from liposomes upon laser stimulation, and adapted to mimic the intricate dynamics of neurotransmission ex vivo in brain preparations. However, to induce a physiological response in vivo requires the degree of temporal precision afforded by laser stimulation, but with a greater depth of penetration through tissue. Here we report that the attachment of hollow gold nanoshells to the surface of robust liposomes results in a construct that is highly sensitive to ultrasonic stimulation. The resulting construct can be remotely triggered by low intensity, therapeutic ultrasound. To our knowledge, this is the first example of nanoparticle-liposome system that can be activated by both laser and acoustic stimulation. The system is capable of encapsulating the neurochemical dopamine, and repeatedly releasing small amounts on-demand in a circulating environment, allowing for precise spatiotemporal control over the release profile

Active propagation of dendritic electrical signals in C. elegans

Active propagation of electrical signals in C. elegans neurons requires ion channels capable of regenerating membrane potentials. Here we report regenerative depolarization of a major gustatory sensory neuron, ASEL. Whole-cell patch-clamp recordings in vivo showed supra linear depolarization of ASEL upon current injection. Furthermore, stimulation of animal\u27s nose with NaCI evoked all-ornone membrane depolarization in ASEL. Mutant analysis showed that EGL-19, the oil subunit of L-type voltage-gated Ca2+ channels, is essential for regenerative depolarization of ASEL. ASEL-specific knock-down of EGL-19 by RNAi demonstrated that EGL-19 functions in C. elegans chemotaxis along an NaCI gradient. These results demonstrate that a natural substance induces regenerative all-or-none electrical signals in dendrites, and that these signals are essential for activation of sensory neurons for chemotaxis. As in other vertebrate and invertebrate nervous systems, active information processing in dendrites occurs in C. elegans, and is necessary for adaptive behavior

An On-Demand Drug Delivery System for Control of Epileptiform Seizures

Drug delivery systems have the potential to deliver high concentrations of drug to target areas on demand, while elsewhere and at other times encapsulating the drug, to limit unwanted actions. Here we show proof of concept in vivo and ex vivo tests of a novel drug delivery system based on hollow-gold nanoparticles tethered to liposomes (HGN-liposomes), which become transiently permeable when activated by optical or acoustic stimulation. We show that laser or ultrasound simulation of HGN-liposomes loaded with the GABAA receptor agonist, muscimol, triggers rapid and repeatable release in a sufficient concentration to inhibit neurons and suppress seizure activity. In particular, laser-stimulated release of muscimol from previously injected HGN-liposomes caused subsecond hyperpolarizations of the membrane potential of hippocampal pyramidal neurons, measured by whole cell intracellular recordings with patch electrodes. In hippocampal slices and hippocampal–entorhinal cortical wedges, seizure activity was immediately suppressed by muscimol release from HGN-liposomes triggered by laser or ultrasound pulses. After intravenous injection of HGN-liposomes in whole anesthetized rats, ultrasound stimulation applied to the brain through the dura attenuated the seizure activity induced by pentylenetetrazol. Ultrasound alone, or HGN-liposomes without ultrasound stimulation, had no effect. Intracerebrally-injected HGN-liposomes containing kainic acid retained their contents for at least one week, without damage to surrounding tissue. Thus, we demonstrate the feasibility of precise temporal control over exposure of neurons to the drug, potentially enabling therapeutic effects without continuous exposure. For future application, studies on the pharmacokinetics, pharmacodynamics, and toxicity of HGN-liposomes and their constituents, together with improved methods of targeting, are needed, to determine the utility and safety of the technology in humans

The QKI-6 RNA Binding Protein Regulates Actin-interacting Protein-1 mRNA Stability during Oligodendrocyte Differentiation

We identify new mRNA targets for the QKI-6 RNA binding proteins using an unbiased approach. We show that AIP-1 mRNA is bound by QKI-6 within its 3′-UTR. This regulation is observed in oligodendrocytes and it is essential for oligodendrocyte process outgrowth

25th annual computational neuroscience meeting: CNS-2016

The same neuron may play different functional roles in the neural circuits to which it belongs. For example, neurons in the Tritonia pedal ganglia may participate in variable phases of the swim motor rhythms [1]. While such neuronal functional variability is likely to play a major role the delivery of the functionality of neural systems, it is difficult to study it in most nervous systems. We work on the pyloric rhythm network of the crustacean stomatogastric ganglion (STG) [2]. Typically network models of the STG treat neurons of the same functional type as a single model neuron (e.g. PD neurons), assuming the same conductance parameters for these neurons and implying their synchronous firing [3, 4]. However, simultaneous recording of PD neurons shows differences between the timings of spikes of these neurons. This may indicate functional variability of these neurons. Here we modelled separately the two PD neurons of the STG in a multi-neuron model of the pyloric network. Our neuron models comply with known correlations between conductance parameters of ionic currents. Our results reproduce the experimental finding of increasing spike time distance between spikes originating from the two model PD neurons during their synchronised burst phase. The PD neuron with the larger calcium conductance generates its spikes before the other PD neuron. Larger potassium conductance values in the follower neuron imply longer delays between spikes, see Fig. 17.Neuromodulators change the conductance parameters of neurons and maintain the ratios of these parameters [5]. Our results show that such changes may shift the individual contribution of two PD neurons to the PD-phase of the pyloric rhythm altering their functionality within this rhythm. Our work paves the way towards an accessible experimental and computational framework for the analysis of the mechanisms and impact of functional variability of neurons within the neural circuits to which they belong