Abstract Ionic currents, whether measured as conductance amplitude or as ion channel transcript levels, can vary many-fold within a population of identified neurons. This variability has been observed in multiple invertebrate neuronal types, but they do so in a coordinated manner such that their magnitudes are correlated. These conductance correlations are thought to reflect a tight homeostasis of cellular excitability that enhances the robustness and stability of neuronal activity over long stretches of time. Notably, although such ionic current correlations are well documented in invertebrates, they have not been reported in vertebrates. Here we demonstrate with two examples, identified mouse hippocampal granule cells and cholinergic basal forebrain neurons, that ionic current correlations is a ubiquitous phenomenon expressed by a number of species across phyla.
Neuronal systems that are involved in reinforcement learning must solve the temporal credit assignment problem, i.e., how is a stimulus associated with a reward that is delayed in time? Theoretical studies [1-3] have postulated that neural activity underlying learning ‘tags’ synapses with an ‘eligibility trace’, and that the subsequent arrival of a reward converts the eligibility traces into actual modification of synaptic efficacies. While eligibility traces provide one simple solution to the temporal credit assignment problem, they alone do not constitute a stable learning rule because there is no other mechanism indicating when learning should cease. In order to attain stability, rules involving eligibility traces often assume that once the association is learned, further learning is prevented via an inhibition of the reward stimulus [1,3,4]. Although synaptic plasticity is responsible for reinforcement learning in the brain, theories of reinforcement learning are generally abstract and involve neither neurons nor synapses. Furthermore, biophysical theories of synaptic plasticity typically model unsupervised learning and ignore the contribution of reinforcement. Here we describe a biophysically based theory of reinforcementmodulated synaptic plasticity and postulate the existence of two eligibility traces with different temporal profiles: one corresponding to the induction of LTP, and the other to the induction of LTD. The traces have different kinetics and their difference in magnitude at the time of reward determines if synaptic modification will correspond to LTP or LTD. Due to the difference in their decay rates, the LTP and LTD traces can exhibit temporal competition at the reward time and thus provides a mechanism for stable reinforcement learning without the need to inhibit reward. We test this novel reinforcement-learning rule on an experimentally motivated model of a recurrent cortical network [5], and compare the model results to experimental results at both the cellular and circuit levels. We further suggest that these eligibility traces are implemented via kinases and phosphatases, thus accounting for results at both the cellular and system levels.
Abstract Reinforcement allows organisms to learn which stimuli predict subsequent biological relevance. Hebbian mechanisms of synaptic plasticity are insufficient to account for reinforced learning because neuromodulators signaling biological relevance are delayed with respect to the neural activity associated with the stimulus. A theoretical solution is the concept of eligibility traces (eTraces), silent synaptic processes elicited by activity which upon arrival of a neuromodulator are converted into a lasting change in synaptic strength. Previously we demonstrated in visual cortical slices the Hebbian induction of eTraces and their conversion into LTP and LTD by the retroactive action of norepinephrine and serotonin Here we show in vivo in V1 that the induction of eTraces and their conversion to LTP/D by norepinephrine and serotonin respectively potentiates and depresses visual responses. We also show that the integrity of this process is crucial for ocular dominance plasticity, a canonical model of experience-dependent plasticity.
J. Neurochem. (2010) 115, 1215-1221.Synaptic dysfunction is widely thought to be a pathogenic precursor to neurodegeneration in Alzheimer's disease (AD), and the extent of synaptic loss provides the best correlate for the severity of dementia in AD patients. Presenilins 1 and 2 are the major causative genes of early-onset familial AD. Conditional inactivation of presenilins in the adult cerebral cortex results in synaptic dysfunction and memory impairment, followed by age-dependent neurodegeneration. To characterize further the consequence of presenilin inactivation in the synapse, we evaluated the temporal development of pre-synaptic and post-synaptic deficits in the Schaeffer-collateral pathway of presenilin conditional double knockout (PS cDKO) mice prior to onset of neurodegeneration. Following presenilin inactivation at 4 weeks, synaptic facilitation and probability of neurotransmitter release are impaired in PS cDKO mice at 5 weeks of age, whereas post-synaptic NMDA receptor (NMDAR)-mediated responses are normal at 5 weeks but impaired at 6 weeks of age. Long-term potentiation induced by theta burst stimulation is also reduced in PS cDKO mice at 6 weeks of age. These results show that loss of presenilins results in pre-synaptic deficits in short-term plasticity and probability of neurotransmitter release prior to post-synaptic NMDAR dysfunction, raising the possibility that presenilins may regulate post-synaptic NMDAR function in part via a trans-synaptic mechanism.
ABSTRACT Altered neural excitability is considered a prominent contributing factor to cognitive decline during aging. A clear example is the excess neural activity observed in several temporal lobe structures of cognitively impaired older individuals in rodents and humans. At a cellular level, aging-related changes in mechanisms regulating intrinsic excitability have been well examined in pyramidal cells of the CA1 hippocampal subfield. Studies in the inbred Fisher 344 rat strain document an age-related increase in the slow afterhyperpolarization (AHP) that normally occurs after a burst of action potentials, and serves to reduce subsequent firing. We evaluated the status of the AHP in the outbred Long-Evans rat, a well-established model for studing individual differences in neurocognitive aging. In contrast to the findings reported in the Fisher 344 rats, in the Long-Evan rats we detected a selective reduction in AHP in cognitively impaired aged individuals. We discuss plausible scenarios to account for these differences and also discuss possible implications of these differences.
Age-dependent alterations in the induction of long-term potentiation (LTP) are well documented, providing a likely neural basis for memory decline associated with aging. Studies of neural plasticity are also important to understand the neural basis of individual differences in aging, ranging from significant cognitive impairment to preservation of function on a par with younger adults. To examine the cellular mechanisms that distinguish such outcomes, we studied the induction of LTP in male outbred young and aged rats behaviorally characterized in hippocampal-dependent spatial learning. We evaluated, in vitro , the magnitude of NMDA receptor (NMDAR)-dependent and -independent forms of LTP induced in the Schaffer collateral to CA1 synapses. We found that age substantially reduces NMDAR-dependent LTP across the spectrum of cognitive outcomes, whereas increased NMDAR-independent LTP occurs distinctively in high-performing aged rats. Moreover, in young rats, behavioral performance correlates strongly with the magnitude of NMDAR-LTP, whereas NMDAR-independent LTP correlates with behavioral performance only in aged rats. Together with similar previous findings on the mechanisms for LTD in this model, these results support the notion that a shift from NMDAR-dependent to NMDAR-independent mechanisms for neural plasticity during aging is associated with better cognitive outcomes.
'/%3e%3cuse xlink:href='%23a' transform='scale(-1 1)'/%3e%3c/g%3e%3cuse xlink:href='%23b' transform='rotate(72)'/%3e%3c/g%3e%3cuse xlink:href='%23b' transform='rotate(-72)'/%3e%3cuse xlink:href='%23c' transform='rotate(144)'/%3e%3c/svg%3e)