Aging-Related Alterations to Persistent Firing in the Lateral Entorhinal Cortex Contribute to Deficits in Temporal Associative Memory.

With aging comes a myriad of different disorders, and cognitive decline is one of them. Studies have consistently shown a decline amongst aged subjects in their ability to acquire and maintain temporal associative memory. Defined as the memory of the association between two objects that are separated in time, temporal associative memory is dependent on neocortical structures such as the prefrontal cortex and temporal lobe structures. For this memory to be acquired, a mental trace of the first stimulus is necessary to bridge the temporal gap so the two stimuli can be properly associated. Persistent firing, the ability of the neuron to continue to fire action potentials even after the termination of a triggering stimulus, is one mechanism that is posited to support this mental trace. A recent study demonstrated a decline in persistent firing ability in pyramidal neurons of layer III of the lateral entorhinal cortex with aging, contributing to learning impairments in temporal associative memory acquisition. In this work, we explore the potential ways persistent firing in lateral entorhinal cortex (LEC) III supports temporal associative memory, and how aging may disrupt this mechanism within the temporal lobe system, resulting in impairment in this crucial behavior.

Persistent firing in LEC III neurons is differentially modulated by learning and aging.

Whether and how persistent firing in lateral entorhinal cortex layer III (LEC III) supports temporal associative learning is still unknown. In this study, persistent firing was evoked in vitro from LEC III neurons from young and aged rats that were behaviorally naive or trained on trace eyeblink conditioning. Persistent firing ability from neurons from behaviorally naive aged rats was lower compared to neurons from young rats. Neurons from learning impaired aged animals also exhibited reduced persistent firing capacity, which may contribute to aging-related learning impairments. Successful acquisition of the trace eyeblink task, however, increased persistent firing ability in both young and aged rats. These changes in persistent firing ability are due to changes to the afterdepolarization, which may in turn be modulated by the postburst afterhyperpolarization. Together, these data indicate that successful learning increases persistent firing ability and decreases in persistent firing ability contribute to learning impairments in aging.

Intrinsic Excitability Increase in Cerebellar Purkinje Cells after Delay Eye-Blink Conditioning in Mice.

Cerebellar-based learning is thought to rely on synaptic plasticity, particularly at synaptic inputs to Purkinje cells. Recently, however, other complementary mechanisms have been identified. Intrinsic plasticity is one such mechanism, and depends in part on the downregulation of calcium-dependent SK-type K+ channels, which contribute to a medium-slow afterhyperpolarization (AHP) after spike bursts, regulating membrane excitability. In the hippocampus, intrinsic plasticity plays a role in trace eye-blink conditioning; however, corresponding excitability changes in the cerebellum in associative learning, such as in trace or delay eye-blink conditioning, are less well studied. Whole-cell patch-clamp recordings were obtained from Purkinje cells in cerebellar slices prepared from male mice ∼48 h after they learned a delay eye-blink conditioning task. Over a period of repeated training sessions, mice received either paired trials of a tone coterminating with a periorbital shock (conditioning) or trials in which these stimuli were randomly presented in an unpaired manner (pseudoconditioning). Purkinje cells from conditioned mice show a significantly reduced AHP after trains of parallel fiber stimuli and after climbing fiber evoked complex spikes. The number of spikelets in the complex spike waveform is increased after conditioning. Moreover, we find that SK-dependent intrinsic plasticity is occluded in conditioned, but not pseudoconditioned mice. These findings show that excitability is enhanced in Purkinje cells after delay eye-blink conditioning, and point toward a downregulation of SK channels as a potential underlying mechanism. The observation that this learning effect lasts at least up to 2 d after training shows that intrinsic plasticity regulates excitability in the long term.SIGNIFICANCE STATEMENT Plasticity of membrane excitability ("intrinsic plasticity") has been observed in invertebrate and vertebrate neurons, coinduced with synaptic plasticity or in isolation. Although the cellular phenomenon per se is well established, it remains unclear what role intrinsic plasticity plays in learning and if it even persists long enough to serve functions in engram physiology beyond aiding synaptic plasticity. Here, we demonstrate that cerebellar Purkinje cells upregulate excitability in delay eye-blink conditioning, a form of motor learning. This plasticity is observed 48 h after training and alters synaptically evoked spike firing and integrative properties of these neurons. These findings show that intrinsic plasticity enhances the spike firing output of Purkinje cells and persists over the course of days.

Whisker-signaled Eyeblink Classical Conditioning in Head-fixed Mice.

Eyeblink conditioning is a common paradigm for investigating the neural mechanisms underlying learning and memory. To better utilize the extensive repertoire of scientific techniques available to study learning and memory at the cellular level, it is ideal to have a stable cranial platform. Because mice do not readily tolerate restraint, they are usually trained while moving about freely in a chamber. Conditioned stimulus (CS) and unconditioned stimulus (US) information are delivered and eyeblink responses recorded via a tether connected to the mouse's head. In the head-fixed apparatus presented here, mice are allowed to run as they desire while their heads are secured to facilitate experimentation. Reliable conditioning of the eyeblink response is obtained with this training apparatus, which allows for the delivery of whisker stimulation as the CS, a periorbital electrical shock as the US, and analysis of electromyographic (EMG) activity from the eyelid to detect blink responses.

Surfing for juvenile idiopathic arthritis: perspectives on quality and content of information on the Internet.

OBJECTIVE: To determine the quality and content of English language Internet information about juvenile idiopathic arthritis (JIA) from the perspectives of consumers and healthcare professionals. METHODS: Key words relevant to JIA were searched across 10 search engines. Quality of information was appraised independently by 2 health professionals, 1 young adult with JIA, and a parent using the DISCERN tool. Concordance of the website content (i.e., accuracy and completeness) with available evidence about the management of JIA was determined. Readability was determined using Flesch-Kincaid grade level and Reading Ease Score. RESULTS: Out of the 3000 Web pages accessed, only 58 unique sites met the inclusion criteria. Of these sites only 16 had DISCERN scores above 50% (indicating fair quality). These sites were then rated by consumers. Most sites targeted parents and none were specifically developed for youth with JIA. The overall quality of website information was fair, with a mean DISCERN quality rating score of 48.92 out of 75 (+/- 6.56, range 34.0-59.5). Overall completeness of sites was 9.07 out of 16 (+/- 2.28, range 5.25-13.25) and accuracy was 3.09 out of 4 (+/- 0.86, range 2-4), indicating a moderate level of accuracy. Average Flesch-Kincaid grade level and Reading Ease Score were 11.48 (+/- 0.74, range 10.1-12.0) and 36.36 (+/- 10.86, range 6.30-48.1), respectively, indicating that the material was difficult to read. CONCLUSION: Our study highlights the paucity of high quality Internet health information at an appropriate reading level for youth with JIA and their parents.