by Jochen Meier, Frontiers in Molecular Neuroscience, Specialty Chief Editor
Thanks to the Frontiers Travel Award I am providing herewith an overview and some highlights of the Winter Conference on Neural Plasticity WCNP, Sunday January 31 – Friday February 05, Maui Hawaii.
Janelle C. LeBoutillier and Ted L. Petit again did a great job and organized this conference which took place at the Sheraton Hotel Ka’anapali (see: http://www.utsc.utoronto.ca/~wcnp/ ). It was an intriguing international conference with approximately 75 participants from all over the world. This post shall provide an overview of recent research highlights covering network, systems and behavioral neuroscience with particular focus on learning and memory, as well as cellular and molecular mechanisms of neural plasticity in health and disease. However, due to confidentiality issues this blog can unfortunately not be exhaustive, but all the contributions blogged here are authorized.
Sunday – New Concepts
The conference started out with the New Concepts Session on Sunday evening and covered heterogeneous topics. Michel Chopp was giving some exciting insights into exosome/miR therapy for neural injury after TBI, showing that the miRNA content of exosomes derived from MSCs promote neurovascular remodeling and recovery after TBI.
Eric Dumont spoke about the role of brain-derived estradiol in gating bi-directional plasticity at oval bed nucleus of the stria terminalis GABA synapses where low frequency stimulation induces iLTP through local synthesis of E2, which could trigger anxiety. Charles Hoeffer discussed non-canonical translation in neural plasticity, showing some stimulating results about Arc- and VEGF-virus dependent monitoring of CAP- and IRES-dependent protein translation using bicistronic fluorescent protein-coding constructs. Stephen Lomber discussed changes in cortical cartography following hearing loss and restoration in cat brains. Interestingly, auditory cortical structure is affected following acute hearing loss after 7 days of normal hearing after birth.
However, in congenitally deaf animals, the structure is also affected (though the entire auditory cortex tends to be generally smaller. Impressively, the auditory cortex of congenitally deaf animals with cochlear implants is similar to the auditory cortex of acute hearing loss-exposed cats. Sarah Neuner presented a novel systems genetics resource for the identification of potential modifiers of familial AD severity in a genetically diverse mouse panel. When combined with existing human risk-based genomics analyses with collaborator Matt Huentelman, this approach uncovered novel variants in Ascc3 associated with the risk of late-onset AD in a human population. Reha Erzurumlu discussed functional consequences of bilateral facial maps along the thalamocortical system.
There were also spontaneous presentations “from the floor”: Cam Teskey spoke about cannabis use “that is on the rise”. He presented data about its impact on locomotion and motor maps. Motor map size changes dose-dependently, but rats show normal motor control and success rate when reaching for a food pellet. Nanthia A. Suthana showed intracranial EEG and theta oscillations in humans during ambulatory movement and presented a new method for wireless intracranial recording and stimulation of brain activity.
Monday morning – Memory enhancement
Concepts, targets, and Therapeutic Utility Michael Yassa addressed the intriguing question about pattern completion and separation using tests where individuals have to discriminate “old, similar, and new pictures”. Wrong declared “old” similar objects (lure objects) provided most suitable readout for pattern separation performance, which is compromised in adult or aged subjects. A neural correlate of this phenomenon, as revealed by fMRI, may be hyperactivity in hippocampal Dentate Gyrus and CA3 regions.
Then, he showed that neuropeptide Y-coding AAV improves memory as well as does Levetiracetam (LEV). LEV actually rescues memory not only in the hAPP J20 mouse model of Alzheimer’s disease but also in patients with aMCI (amnestic mild cognitive impairment). He also spend some time on mechanisms of pattern separation by showing that adult neurogenesis in the Dentate Gyrus correlates with pattern separation performance. Furthermore, arousal (norepinephrine), mild exercise as well as caffeine all lead to better discrimination (separation), while they do not have an effect on retrieval.
Monday afternoon – Mechanisms of place cells
Across species comparison Elizabeth Buffalo presented work from her lab investigating hippocampal activity in monkeys trained to use a joystick to navigate in virtual space, performing tasks of free foraging and spatial memory. Nachum Ulanovsky presented studies with bats. 3D space cells, head direction cells were identified in dorsal presubiculum, and 3D grid cells could encode distance, not position. Navigation from A to B requires encoding of the goal position, hence goal-direction cells do exist, but goal direction tuning is not explained by place tuning.
Rather, goal direction and goal distance give rise to a vectorial representation. Experiments involving a curtin between bat and object revealed that direction is memory (mental), not sensory, based. In contrast to other species, there were no movement related oscillations. Nevertheless, phase-locked firing to the field potential occurs. Even precession firing exists, which was conceived somewhat surprising but can actually be explained even without periodicity of an underlying network field potential oscillation.
Tuesday morning – TDP-43 related neurologic disorders
ALS and dementia Daniel Perl spoke about transactive response (TAR) RNA/DNA binding protein TDP-43 and its involvement in neurodegenerative diseases. He presented the very interesting case of the Guam Island in the Western Pacific, where the native population has a very high incidence of amyotrophic lateral sclerosis (ALS) as well as a unique disorder called Parkinsonism/Dementia complex (PDC) of Guam. These patients characteristically show the presence of large numbers of neurofibrillary tangles (no amyloid-beta plaques). The reason for the acquired, environmentally induced, ALS/PDC is not known, but it is generally thought that 20 years residency on the island is required to develop the disease.
Many fundamental aspects of the outbreak have changed in the past twenty years. Personal note: The acquired Guam ALS/PDC is a proteasomal disease which involves cell stress, calpain activation (for example by pesticides or mercury), and TDP-43 cleavage and resulting protein deposits. For more information see also: http://www.weriguam.org/programs/water-quality-production-and-distribution/page/recent-publications.html, and Denton, G.R.W., Trianni, M.S., Bearden, B.G., Houk, P.C. and Starmer, J.A. (2011). Impact of a Medical Waste Incinerator on Mercury Levels in Lagoon Fish from a Small Tropical Island in the Western Pacific. Journal of Toxicology and Environmental Health Part A, 74: 823–827. Dr. Perl compared the neurodegenerative diseases seen on Guam with chronic traumatic encephalopathy (CTE), another form of acquired tauopathy with some similarities to Guam ALS/PDC.
Elliott Mufson focused on chronic traumatic encephalopathy (CTE) as a tauopathy, which develops after continued head trauma sustained in the military or playing contact sports such as American football. CTE brains shown tau positive lesions in the cortex but little is known about the effects of CTE upon structures located deep within the brain such as the cholinergic basal forebrain cortical projection cells involved in memory function. The appearance of early tau markers, oligomeric (TOC1) and phosphatase-activating domain (PAC) in dendrites of cholinergic basal forebrain neurons early in the onset of CTE, suggests that the disease process is not initiated in the soma of these neurons but is activated via signals travelling within fiber tracts.
Although abnormal TDP-43, a novel potential toxic protein is found in the neurons of patients with Alzheimer’s disease, frontal temporal dementia and ALS, similar changes were not seen in basal forebrain cholinergic neurons in CTE. Robert Bowser discussed mechanisms of cognitive impairment in ALS patients, genetic causes, mutations in the RNA binding proteins TDP-43 and FUS (Fused in Sarcoma/Translocated in Sarcoma) that are involved in gene transcription, RNA splicing, miRNA processing that cause ALS and frontotemporal lobar dementia (FTLD).
Chronic stress of neurons that occurs during ALS and FTLD induces the formation of cytoplasmic stress granules containing TDP-43, and these cytoplasmic stress granules may be a prelude to the inclusions detected in post-mortem brain tissue. Another RNA binding protein, RBM45, was also detected in cytoplasmic stress granules of motor neurons in ALS patients. In addition to cytoplasmic stress, the nucleus also undergoes stress and far less is known about how nuclear stress impacts neuronal survival. Under conditions of stress, TDP-43 co-localizes with SMN to nuclear speckles, and both TDP-43 and FUS co-localize to paraspeckles within the nucleus. RBM45 co-localizes with heat shock factor 1 (HSF1) in nuclear stress bodies, a distinct nuclear sub-structure and separate from TDP-43 or FUS containing nuclear structures. Using post-mortem tissue sections, RBM45 and scaffold attachment factor B (SAFB) containing nuclear stress bodies are detected in dentate granule cells in ALS, FTLD and AD patients.
The dentate contained the highest concentration of these nuclear stress bodies, suggesting that this region is under nuclear stress across multiple neurodegenerative diseases.
Wednesday morning – Electrical brain stimulation to enhance learning and memory
Barbara Knowlton said that interleaved practice (over several days) leads to better retention of memory. Sensorimotor areas show more activation in case of interleaved practice. Before and after training, paired-pulse transcranial magnetic stimulation (TMS) was used to measure changes in intracortical inhibition and excitation.
Interleaved practice leads to more excitability at test day 5.
Sensorimotor skill transfer seems to involve the same mechanisms as above, but measurement of performance of sequence-specific learning with new variables also involves the cerebellum (more activation in this area was detected using fMRI). Manipulation of cerebellar function with tDCS (anodal stimulation [which increases action potential discharge] during practice followed by overnight consolidation) improves transfer of sequence learning measured the following day. Vince Clark investigated recognition of hidden objects in a target detection task and used fMRI to reveal frontal and parietal cortical areas involved in learning. Stimulation with anodal tDCS (glutamate increase measured experimentally) of right inferior frontal cortex doubled learning performance in the hidden object task.
When stimulation electrodes were placed over the temporal cortex no effect on performance was observed. In the future, he wants to investigate some of the possible 890 quintillion different stimulation protocols and their effects on different memory performance tasks for the purpose of memory enhancement and treatment of other forms of brain and mental illness in humans. Nanthia Suthana presented some intriguing and inspiring methods for, and mechanisms of memory enhancement. In particular, she showed that stimulation of entorhinal white matter (perforant pathway in humans), not gray matter, improves spatial memory in virtual reality, while direct stimulation of the hippocampus did not enhance memory. Furthermore, she presented a new device for micro-/macrostimulation and single unit recordings and showed that stimulation with 50 Hz, 300 ms pulse width, 5 sec on/off (the stimulation intensity was individually adjusted to avoid after-discharges) of perforant path during learning improves memory performance. High-resolution CT and MRI before and after implantation allowed precise localization of electrode positions within the hippocampus and entorhinal area. Hippocampal stimulation or stimulation of entorhinal gray matter decreased memory performance whereas white matter stimulation was key to enhance memory.
Theta-burst stimulation of the right entorhinal area improved memory specificity. Regarding the mechanisms, she showed that hippocampal CA1 theta-gamma (in the 74-150 Hz gamma range) coupling increased during learning of subsequently collected items, and that entorhinal stimulation increased hippocampal theta-gamma coupling. Her outlook and presentation of ongoing projects involved development of a wireless and inductive (no batteries required) and easily implantable devices for intracranial recording and stimulation for memory enhancement and therapeutic purpose, for example in temporal lobe epilepsy. Joel Voss finally addressed the posterior hippocampal cortical network and used stimulation of a lateral parietal cortex region that is connected with the hippocampus. High frequency excitatory 20 Hz during 20 min stimulation improved performance and precision in an associative face/word pair test in electrically stimulated test persons.
Wednesday afternoon – Memory
Organization and control Howard Eichenbaum provided a systems analysis of prefrontal-hippocampal dialog that supports context-guided memory retrieval, whereby the hippocampus is responsible for remembering items on the list of explicit memories, and the medial prefrontal cortex (mPFC) suppresses intrusions from other lists. He presented data obtained with context guided memory task and in vivo recording in dorsal hippocampus (dHPC) in animals with or without muscimol injection in mPFC. Without muscimol, dHPC cells respond to specific objects in their context but, with musical-inactivtion of mPFC, these cells lost their object specificity.Then, he switched to the ventral hippocampus (vHPC), where activated place fields are larger than in the dorsal hippocampus and represent contextual information. Theta amplitude local field potential (LFP) cross-correlation revealed that the ventral hippocampus is leading the mPFC by 25-30 ms when animals were cued with a context, then mPFC leads HPC when animals sample the objects, altogether generating a circle of information flow from mPFC to dHPC to vHPC and back to mPFC. All of this holds true for theta, not other frequencies. Finally, he suggested that mPFC projecting to the lateral and medial entorhinal cortex suppresses inappropriate object representations. Joel Voss used fMRI to show involvement of hippocampus in memory-guided decision making, and Mark D’Esposito discussed large-scale organization of the brain. Evidence for connectors and HUBs was provided based on large number of fMRI data.
Actually, stroke patients with focal lesions in either connector or HUB regions experience different disabilities, with damage to connectors basically decreasing modularity. In fact, persons with a more modular brain have a higher working memory capacity. Is this connector / HUB classification a major advance compared to Brodmann area classification of brain regions?
Thursday morning – Plasticity of interneuron networks
Role of chemical and electrical synapses Michael Häusser’s talk was entitled “The coupled Olive: a moveable feast”. It was about gap junctions in the inferior olive which are located just a few 100 nm close to chemical symmetric and asymmetric synapses. The question was asked as to whether glutamatergic synapses can modulate olivary electrical synapses. Electrical stimulation with 50 times at 1 Hz led to long-term depression (LTD) of electrical coupling conductance. Postsynaptic stimulation was not sufficient but required NMDA receptor activation (APV). The calcium chelator BAPTA in intracellular solution also blocked LTD as did KN62 (calcium calmodulin kinase II inhibitor). GABA type A or type B receptor activation were not involved in this process. Remarkably, the glutamatergic responses themselves were not affected, meaning that the chemical glutamatergic synapses in the vicinity of gap junctions are instructing LTD of the electrical synapse.
Thursday afternoon – Hippocampal contributions to fear and anxiety
Brian Wiltgen challenged the idea that dorsal and ventral hippocampi specifically control spatial and emotional (anxiety), respectively, learning. Earlier studies showed that animals with lesioned ventral hippocampus do not show anxiety-related behavior in the Elevated Plus Maze test. However, context fear learning should be dependent on both spatial and emotional information and thus involve both dorsal and ventral hippocampi. Actually, the dorsal hippocampus can modulate fear independent of the ventral hippocampus, through retrosplenial cortex, medial prefrontal cortex and amygdala. Even when the dorsal hippocampus is inactivated, the retrosplenial cortex can drive freezing. Thus, dorsal and ventral hippocampi cooperate in context fear learning, that is the hippocampus conveys small-scale spatial information, while the ventral hippocampus conveys large-scale information about regions related with anxiety (see also above, place fields, Howard Eichenbaum).
Rene Hen spoke about the role of the ventral dentate gyrus in mood and anxiety. Why? Because serotonin 5-HT1A receptor expression in the ventral hippocampus are targeted by antidepressants. POMC-Cre mice were used to knockout 5-HT1A receptors specifically in the dentate gyrus. No effect of chronic fluoxetine in these mice in forced swimming test, contextual fear conditioning, novelty suppressed feeding (NSF), and other tests were observed.
Rescue of 5-HT1A expression using viral constructs in these mice rescued normal behavior, demonstrating a specific effect of 5-HT1A receptors in the dentate gyrus. Neurogenesis in the ventral dentate gyrus was shown to be necessary for some of the behavioral effects of antidepressants. Effects of fluoxetine in the NSF test was blocked by ventral irradiation, ablating neurogenesis. Furthermore, activation of the ventral dentate produces anxiolytic effects as optical stimulation of ventral dentate gyrus increases exploration of elevated open arms, i.e. leading to reduced anxiety-related behavior. Use of mini-microscopes (see above, New Concepts Session) shows that ventral hippocampal neurons are more active in terms of calcium transients when mice explore open arms in the Elevated Plus Maze test. Open arm responsive cells are enriched in the ventral hippocampus relative to the dorsal hippocampus. There are non-overlapping cell populations in the ventral hippocampus that specifically project to lateral hypothalamus or basomedial amygdala. The ventral hippocampal projections to lateral hypothalamus impact innate anxiety but not contextual fear encoding, whereas projections to the basomedial amygdala impacts contextual fear encoding but not innate anxiety.
Isabel Muzzio showed that different hippocampal dorsal cells remapped during different stages of fear learning. There were cells that only remapped during conditioning, cells that only remapped during extinction, cells that remapped both during conditioning and extinction, and cells that remain stable and did not change during learning. This indicates that safe, fearful, and static memory traces coexist during extinction in the dorsal hippocampus. Although place fields in the ventral hippocampus are much broader relative to the dorsal hippocampus, and the spatial information encoded by the ventral hippocampus may thus not be as precisely represented at the single cell level as it is in the dorsal hippocampus, population activity in the ventral hippocampus actually contains precise spatial information.
The redundancy in spatial representation along the longitudinal hippocampal axis may provide a mnemonic advantage that allows this region to overcome the interference-generalization conflict inherent in memory. Stephen Maren finally investigated renewal of contextual fear memory after extinction. It turned out that ventral hippocampus potently inhibits infralimbic cortex neurons (ventromedial prefrontal cortex), and that blocking GABAergic inhibition in the cortex impairs renewal of fear memory after extinction. Consistently, pharmacogenetic silencing of ventral hippocampus impaired fear renewal.
Friday morning – Molecular mechanisms underlying long-term memory processes, drug-seeking behavior, and diseases of the brain
Gavin Rumbaugh Gavin Rumbaugh discussed animal models that are based on mutations identified in cases with severe idiopathic childhood cognitive disorders, focusing on postsynaptic neuron-enriched RasGAP
SYNGAP1 which can suppress synapse function and has been linked to intellectual disability, autism spectrum disorder, epileptic encephalopathy, and schizophrenia. Syngap1 haploinsufficiency within a critical early postnatal developmental period disrupted the growth and maturation of neocortical excitatory neurons in a cell-layer and brain-region specific manner. Many of the cellular phenotypes described in mutant animals were diametrically opposed. Desynchronized neuronal growth during critical periods drove impairments in sensory-evoked cortical function.
Courtney Miller spoke about addiction and posttraumatic stress disorders and development of appropriate therapeutic strategies which should accelerate memory extinction or block reconsolidation. Because of the limited efficacy of retrieval-based strategies in the clinic to date, suggests Identification of a mechanism unique to drug-associated memory storage to prevent relapse is needed. Behavioral tests for contextual memory associated with drug reward were used for readout. Red sea sponge derived latrunculin A-dependent actin depolimerization was shown to have no effect on established fear memory, but a single latrunculin injection in the amygdala after the training phase (in the presence of methamphetamine, METH) and 15 minutes before the test phase selectively prevented METH seeking behavior and context-induced reinstatement. Intraperitoneal latrunculin A injection would be lethal because of peripheral processes dependent on actin polymerization.
Turned to nonmuscle myosin II, a direct driver of synaptic actin polymerization. Blebbistatin-mediated inhibition of non-muscle myosin II and virus-mediated down-regulation of this protein were furthermore shown to be sufficient to produce long-lasting blockade of METH seeking behavior, including via systemic administration. Open question as to why actin cytoskeleton dynamics affect METH seeking behavior remained. Marcelo Wood presented results about the role of chromatin-regulatory enzymes and the neuron-specific nucleosome remodeling subunit, BAF53b, in synaptic plasticity, memory, and drug-seeking behavior.
BAF53a is involved in myc-dependent transformation of cells into tumor cells and early neuronal development, whereas BAF53b is the dedicated postmitotic neuron specific subunit. Heterozygous BAF53b knockout mice exhibited impaired long-term potentiation (LTP) and long-term memory for object recognition, while no differences in short-term memory, anxiety, and locomotor behavior were observed. Molecular dissection of the signaling mechanisms involved cofilin phosphorylation (actin dynamics) in BAF53b-dependent effects on long-term object recognition memory.
Many open questions remained, including relationship between nucleosome remodeling and BAF53b effects on synaptic function and memory. Actually, BAF53b could also be expressed and function directly at synapses. Eric Klann spoke about regulation of protein translation by eIF2. Cell stress down-regulates general translation but upregulates gene specific translation of uORF-containing mRNAs (e.g. the transcription factor ATF4) through phosphorylation-dependent eIF2 signaling. Restricted deletion of the kinase PERK in the forebrain leads to enhanced LTD while LTP is unaffected. Reversal learning in the Y-maze test is impaired, which decreases cognitive flexibility.
However, immediate reversal learning is normal, suggesting a role for PERK in memory consolidation. An ATF4 luciferase activity assay was used to functionally characterize autism spectrum disorder-associated gene mutations detected in multiple eIF2alpha kinases, which revealed both loss- and gain-of-function effects. Abnormal eIF2 phosphorylation was not restricted to autism spectrum disorder but also occurred in Alzheimer’s disease and ALS. In fact, increased eIF2 phosphorylation was associated with TDP-43 signaling (see above) and neurodegeneration in ALS. Furthermore, deletion of PERK in excitatory forebrain neurons corrects hippocampal synaptic plasticity and spatial memory deficits exhibited by Alzheimer’s disease model mice. Development of a mouse model with conditional expression of the kinase domain of protein kinase R (PKR), a sentinel kinase for cellular stress, is on the way for pharmacogenetic manipulation of eIF2alpha phosphorylation and hence, cell type- and region-specific modulation of mRNA translation, which should be useful for our understanding of the role of de novo protein synthesis in memory processes.
Hope you enjoyed it.