The ability to change strategies in different contexts is a form of behavioral flexibility that is crucial for adaptive behavior. The striatum has been shown to contribute to certain forms of ...behavioral flexibility such as reversal learning. Here we report on the contribution of striatal cholinergic interneurons-a key element in the striatal neuronal circuit-to strategy set-shifting in which an attentional shift from one stimulus dimension to another is required. We made lesions of rat cholinergic interneurons in dorsomedial or ventral striatum using a specific immunotoxin and investigated the effects on set-shifting paradigms and on reversal learning. In shifting to a set that required attention to a previously irrelevant cue, lesions of dorsomedial striatum significantly increased the number of perseverative errors. In this condition, the number of never-reinforced errors was significantly decreased in both types of lesions. When shifting to a set that required attention to a novel cue, rats with ventral striatum lesions made more perseverative errors. Neither lesion impaired learning of the initial response strategy nor a subsequent switch to a new strategy when response choice was indicated by a previously relevant cue. Reversal learning was not affected. These results suggest that in set-shifting the striatal cholinergic interneurons play a fundamental role, which is dissociable between dorsomedial and ventral striatum depending on behavioral context. We propose a common mechanism in which cholinergic interneurons inhibit neurons representing the old strategy and enhance plasticity underlying exploration of a new rule.
Dopamine and glutamate are key neurotransmitters involved in learning and memory mechanisms of the brain. These two neurotransmitter systems converge on nerve cells in the neostriatum. Dopamine ...modulation of activity-dependent plasticity at glutamatergic corticostriatal synapses has been proposed as a cellular mechanism for learning in the neostriatum. The present research investigated the role of specific subtypes of dopamine receptors in long-term potentiation (LTP) in the corticostriatal pathway, using intracellular recording from striatal neurons in a corticostriatal slice preparation. In agreement with previous reports, LTP could be induced reliably under Mg(2+)-free conditions. This Mg(2+)-free LTP was blocked by dopamine depletion and by the dopamine D-1/D-5 receptor antagonist SCH 23390 but was not blocked by the dopamine D-2 receptor antagonist remoxipride or the GABA(A) antagonist picrotoxin. In dopamine-depleted slices, the ability to induce LTP could be restored by bath application of the dopamine D-1/D-5 receptor agonist, SKF 38393. These results show that activation of dopamine D-1/D-5 receptors by either endogenous dopamine or exogenous dopamine agonists is a requirement for the induction of LTP in the corticostriatal pathway. These findings have significance for current understanding of learning and memory mechanisms of the neostriatum and for theoretical understanding of the mechanism of action of drugs used in the treatment of psychotic illnesses and Parkinson's disease.
In the slow channel congenital myasthenic syndrome mutations in genes encoding the muscle acetylcholine receptor give rise to prolonged ion channel activations. The resulting cation overload in the ...postsynaptic region leads to damage of synaptic structures, impaired neuromuscular transmission and fatigable muscle weakness. Previously we identified and characterised in detail the properties of the slow channel syndrome mutation εL221F. Here, using this mutation, we generate a transgenic mouse model for the slow channel syndrome that expresses mutant human ε-subunits harbouring an EGFP tag within the M3–M4 cytoplasmic region, driven by a ~1500bp region of the CHRNB promoter. Fluorescent mutant acetylcholine receptors are assembled, cluster at the motor endplates and give rise to a disease model that mirrors the human condition. Mice demonstrate mild fatigable muscle weakness, prolonged endplate and miniature endplate potentials, and variable degeneration of the postsynaptic membrane. We use our model to investigate ephedrine as a potential treatment. Mice were assessed before and after six weeks on oral ephedrine (serum ephedrine concentration 89±3ng/ml) using an inverted screen test and in vivo electromyography. Treated mice demonstrated modest benefit for screen hang time, and in measures of compound muscle action potentials and mean jitter that did not reach statistical significance. Ephedrine and salbutamol show clear benefit when used in the treatment of DOK7 or COLQ congenital myasthenic syndromes. Our results highlight only a modest potential benefit of these β2-adrenergic receptor agonists for the treatment of the slow channel syndrome.
•We have generated a mouse model of slow channel congenital myasthenic syndrome.•Fluorescent mutant acetylcholine receptors integrate into mouse muscle endplates.•The characteristics of human disease are replicated in the model.•Model shows prolonged endplate current and fatigable weakness.•Oral ephedrine modestly improves neurotransmission and fatigability in model mice.
The analysis of the neural mechanisms responsible for reward-related learning has benefited from recent studies of the effects of dopamine on synaptic plasticity. Dopamine-dependent synaptic ...plasticity may lead to strengthening of selected inputs on the basis of an activity-dependent conjunction of sensory afferent activity, motor output activity, and temporally related firing of dopamine cells. Such plasticity may provide a link between the reward-related firing of dopamine cells and the acquisition of changes in striatal cell activity during learning. This learning mechanism may play a special role in the translation of reward signals into context-dependent response probability or directional bias in movement responses.
Activity-dependent synaptic plasticity occurs in several parts of the basal ganglia. Increasing evidence supports the hypothesis that activity-dependent plasticity underlies the acquisition, ...maintenance, and extinction of certain types of learning in the basal ganglia. This review focuses on synaptic plasticity in the corticostriatal pathway. As in other systems, both long-term potentiation and long-term depression have been described, and intracellular calcium signalling plays an important role in the induction of plasticity. However, intracellular calcium levels do not appear to be the dominating control factor. Dopamine, via intracellular signalling cascades, also plays a crucial role in determining the magnitude and direction of plasticity, and in modulating the requirements for induction. Endocannabinoids also play an important role in mediating presynaptic expression of synaptic depression. Recent studies have highlighted spike-timing dependent plasticity phenomena, which also involve dopamine and endocannabinoid signalling. Despite significant progress in recent years, many important questions remain unanswered, especially in relation to long-term potentiation. Of particular interest is the question of how to link the molecular and cellular mechanisms of synaptic plasticity to learning operations at the systems level, which are expressed behaviourally as reinforcement-related learning.
Positive reinforcement helps to control the acquisition of learned behaviours. Here we report a cellular mechanism in the brain that may underlie the behavioural effects of positive reinforcement. We ...used intracranial self-stimulation (ICSS) as a model of reinforcement learning, in which each rat learns to press a lever that applies reinforcing electrical stimulation to its own substantia nigra. The outputs from neurons of the substantia nigra terminate on neurons in the striatum in close proximity to inputs from the cerebral cortex on the same striatal neurons. We measured the effect of substantia nigra stimulation on these inputs from the cortex to striatal neurons and also on how quickly the rats learned to press the lever. We found that stimulation of the substantia nigra (with the optimal parameters for lever-pressing behaviour) induced potentiation of synapses between the cortex and the striatum, which required activation of dopamine receptors. The degree of potentiation within ten minutes of the ICSS trains was correlated with the time taken by the rats to learn ICSS behaviour. We propose that stimulation of the substantia nigra when the lever is pressed induces a similar potentiation of cortical inputs to the striatum, positively reinforcing the learning of the behaviour by the rats.
Highlights • We recorded extracellular single-unit activity from the striatum of two strains of rat during quiet rest. • Putative identified neuronal subtypes included medium spiny neurons (pMSN) and ...fast-spiking interneurons (pFSI). • pFSI in GH rats showed different basal firing properties and were encountered less frequently than in Wistar controls. • AMPH increased Wistar rat pFSI firing rate, but did not significantly change GH rat pFSI activity.
Growing evidence for declines in wild bees calls for the development and implementation of effective mitigation measures. Enhancing floral resources is a widely accepted measure for promoting bees in ...agricultural landscapes, but effectiveness varies considerably between landscapes and regions. We hypothesize that this variation is mainly driven by a combination of the direct effects of measures on local floral resources and the availability of floral resources in the surrounding landscape. To test this, we established wildflower strips in four European countries, using the same seed mixture of forage plants specifically targeted at bees. We used a before–after control–impact approach to analyse the impacts of wildflower strips on bumblebees, solitary bees and Red List species and examined to what extent effects were affected by local and landscape‐wide floral resource availability, land‐use intensity and landscape complexity. Wildflower strips generally enhanced local bee abundance and richness, including Red‐listed species. Effectiveness of the wildflower strips increased with the local contrast in flower richness created by the strips and furthermore depended on the availability of floral resources in the surrounding landscape, with different patterns for solitary bees and bumblebees. Effects on solitary bees appeared to decrease with increasing amount of late‐season alternative floral resources in the landscape, whereas effects on bumblebees increased with increasing early‐season landscape‐wide floral resource availability. Synthesis and applications. Our study shows that the effects of wildflower strips on bees are largely driven by the extent to which local flower richness is increased. The effectiveness of this measure could therefore be enhanced by maximizing the number of bee forage species in seed mixtures, and by management regimes that effectively maintain flower richness in the strips through the years. In addition, for bumblebees specifically, our study highlights the importance of a continuous supply of food resources throughout the season. Measures that enhance early‐season landscape‐wide floral resource availability, such as the cultivation of oilseed rape, can benefit bumblebees by providing the essential resources for colony establishment and growth in spring. Further research is required to determine whether, and under what conditions, wildflower strips result in actual population‐level effects.
Knowledge of the effect of dopamine on corticostriatal synaptic plasticity has advanced rapidly over the last 5 years. We consider this new knowledge in relation to three factors proposed earlier to ...describe the rules for synaptic plasticity in the corticostriatal pathway. These factors are a phasic increase in dopamine release, presynaptic activity and postsynaptic depolarisation. A function is proposed which relates the amount of dopamine release in the striatum to the modulation of corticostriatal synaptic efficacy. It is argued that this function, and the experimental data from which it arises, are compatible with existing models which associate the reward-related firing of dopamine neurons with changes in corticostriatal synaptic efficacy.
The spiny projection neurons are by far the most numerous type of striatal neuron. In addition to being the principal projection neurons of the striatum, the spiny projection neurons also have an ...extensive network of local axon collaterals by which they make synaptic connections with other striatal projection neurons. However, up to now there has been no direct physiological evidence for functional inhibitory interactions between spiny projection neurons. Here we present new evidence that striatal projection neurons are interconnected by functional inhibitory synapses. To examine the physiological properties of unitary inhibitory postsynaptic potentials (IPSPs), dual intracellular recordings were made from pairs of spiny projection neurons in brain slices of adult rat striatum. Synaptic interactions were found in 9 of 45 pairs of neurons using averages of 200 traces that were triggered by a single presynaptic action potential. In all cases, synaptic interactions were unidirectional, and no bidirectional interactions were detected. Unitary IPSPs evoked by a single presynaptic action potential had a peak amplitude ranging from 157 to 319 microV in different connections (mean: 277 +/- 46 microV, n = 9). The percentage of failures of single action potentials to evoke a unitary IPSP was estimated and ranged from 9 to 63% (mean: 38 +/- 14%, n = 9). Unitary IPSPs were reversibly blocked by bicuculline (n = 4) and had a reversal potential of -62.4 +/- 0.7 mV (n = 5), consistent with GABA-mediated inhibition. The findings of the present study correlate very well with anatomical evidence for local synaptic connectivity between spiny projection neurons and suggest that lateral inhibition plays a significant role in the information processing operations of the striatum.
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