The molecular machinery that translates the messenger RNAs into protein is located in ribosomes. Ribosomes are present within neurons in or near synapses, where they are particularly abundant in postsynaptic sites. Evidence suggests that local protein synthesis is required for the 'strengthening' (increased size and responsivity) of synapses that is believed to be and essential process in the encoding of memories. However, there are many different proteins that regulate protein synthesis and only recently have neuroscientists begun to provide answers the following questions: 1) how does activation of a synapse affects local protein synthesis? 2) what signaling pathways are involved? 3) what are the new proteins synthesized locally? 4) which newly produced proteins are critical for memory consolidation? 5) what are the roles of the newly synthesized proteins in memory consolidation? 6) How is synaptic activity-dependent protein synthesis altered in developmental and neurodegenerative disorders? In this episode I talk with Professor Eric Klann, Director of the Center for Neural Science at New York University, about his laboratory's contributions to the answering of these important questions.

Klann NYU page:

https://as.nyu.edu/faculty/eric-klann.html?challenge=d06e90d7-4d8f-4b88-9d8c-10b73beb60f1

Review article on protein synthesis and memory consolidation

https://pmc.ncbi.nlm.nih.gov/articles/PMC8930706/pdf/nihms-1782052.pdf

Integrated stress response and protein synthesis

https://pmc.ncbi.nlm.nih.gov/articles/PMC10964249/pdf/nihms-1970879.pdf

Neuron translatomes and memory consolidation

https://pmc.ncbi.nlm.nih.gov/articles/PMC13443933/pdf/41467_2026_Article_74455.pdf

Activity-dependent protein synthesis in neurons requires microglial-metabolic coupling.

https://pmc.ncbi.nlm.nih.gov/articles/PMC13245367/pdf/nihms-2176826.pdf

With the advent of new technological approaches and emerging discoveries has come a growing appreciation for the importance of astrocytes in neuroplasticity. In contrast to the chemical synapses between neurons, astrocytes are directly connected by gap junctions comprised of connexin proteins. In the present episode I talk with New York University neuroscientist Melissa Cooper about her research that has revealed roles for astrocyte networks in redistribution of energy substrates in response to injury. Using a clever way of molecular tagging of molecules as they pass through gap junctions in combination with whole brain imaging Melissa has identified astrocyte networks that span long distances and connect different brain regions in patterns that often do not correspond to neuron networks. We talk about the implications of her findings for roles of astrocyte networks in brain function and responses to injury and disease.

LINKS

Redistribution of metabolic resources through astrocyte networks mitigates neurodegenerative stress.:

https://pmc.ncbi.nlm.nih.gov/articles/PMC7414143/pdf/pnas.202009425.pdf

Astrocytes in the mouse brain respond bilaterally to unilateral retinal neurodegeneration.:

https://pmc.ncbi.nlm.nih.gov/articles/PMC11929491/pdf/pnas.202418249.pdf

Astrocytes connect specific brain regions through plastic networks.:

https://pmc.ncbi.nlm.nih.gov/articles/PMC13322983/pdf/41586_2026_Article_10426.pdf

The roundworm C. Elegans has proven to be a valuable organism for advancing understanding of fundamental molecular and cellular mechanisms of aging because of its short lifespan, ease of genetic manipulations, and fully documented cellular organization. During the past 10 years or so Scott Leiser's laboratory at the University of Michigan has made several fascinating discoveries concerning how specific cells in the nervous system and elsewhere respond to environmental challenges in ways that either extend or shorten lifespan. Particularly interesting is evidence that: certain serotonergic and dopaminergic neurons that respond to food odors and availability control aging; that activation of certain touch receptors can counteract lifespan extension by dietary restriction; and that FMOs (flavin monooxygenases) extend lifespan and increase stress resistance. These findings provide new insight into the basic mechanisms of aging and for the development of interventions to extend health span.

LINKS

Leiser Laboratory:

https://medschool.umich.edu/profile/2430/scott-f-leiser

Articles discussed in this podcast

https://pmc.ncbi.nlm.nih.gov/articles/PMC9174215/pdf/41467_2022_Article_30869.pdf

https://pmc.ncbi.nlm.nih.gov/articles/PMC12582246/pdf/pnas.202423780.pdf

https://pmc.ncbi.nlm.nih.gov/articles/PMC11828484/pdf/elife-99971.pdf

https://pmc.ncbi.nlm.nih.gov/articles/PMC12247763/pdf/nihpp-2025.05.04.652087v1.pdf

Astrocytes are known to play important roles in brain energy metabolism and the regulation of neuronal network activities. A single astrocyte has a highly elaborate and expansive morphology which enables it to interact with many thousands of neurons and synapses. Moreover, astrocytes are connected to adjacent astrocytes via gap junctions and evidence suggests that these astrocyte networks may mediate long range communications within and between brain regions. In this episode I talk with University of Montreal neuroscientist Ciaran Murphy-Royal about the rapidly expanding knowledge concerning astrocyte functions in regulating brain functions and responses to environmental conditions with a focus on stress responses. Ciaran's laboratory recently showed that astrocyte activity influences anxiety states and that selective manipulations of astrocyte activity can increase or decrease fear and anxiety. We also talk about how astrocytes may mediate chronic stress-induced memory impairment.

LINKS

Murphy-Royal laboratory:

https://www.murphyroyallab.org/

Amygdala astrocytes control anxiety states:

https://www.cell.com/neuron/fulltext/S0896-6273(26)00163-7?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0896627326001637%3Fshowall%3Dtrue

Male – female differences in astrocyte-mediated stress responses:

https://pmc.ncbi.nlm.nih.gov/articles/PMC12246237/pdf/41467_2025_Article_61643.pdf

Early life stress, astrocyte dysfunction, and fear generalization:

https://pmc.ncbi.nlm.nih.gov/articles/PMC11798576/pdf/elife-99988.pdf

The disease process in Alzheimer's disease involves local inflammatory processes wherein microglia are activated and produce pro-inflammatory cytokines. Accumulations of amyloid beta-peptide promote neuroinflammation by causing oxidative stress and damage to neurons and the microglia react to that damage. In this episode I talk with John Fryer about mechanisms of neuroinflammation and new immunotherapy approaches targeting amyloid in Alzheimer's disease including the use of 'nanobodies' which are small single-domain antibodies produced in camels and adapted for research and therapeutic purposes. John was previously an investigator at the Mayo Clinic and is now Director of the Center for Accelerated Nanotherapeutics in Phoenix. Note that one's risk for Alzheimer's disease is reduced by regular exercise, heart-healthy diets, and keeping intellectually and socially engaged throughout life.

LINKS

Fryer webpage at Tgen:

Articles

https://pmc.ncbi.nlm.nih.gov/articles/PMC5565413/pdf/pnas.201701137.pdf

https://pmc.ncbi.nlm.nih.gov/articles/PMC13148177/pdf/nihms-2168146.pdf

https://alz-journals.onlinelibrary.wiley.com/doi/epdf/10.1002/trc2.70269

https://pmc.ncbi.nlm.nih.gov/articles/PMC13329261/pdf/ALZ-22-e71639.pdf

https://pmc.ncbi.nlm.nih.gov/articles/PMC6122978/pdf/JEM_20180653.pdf

While it has long been known that activity in neural networks in sleep differs from activity during waking hours. EEG recordings have revealed patterns of activity oscillations associated with deep (non-REM) sleep and rapid eye movement (REM) sleep. However, it remains unclear how transitions from wake to sleep and from sleep to wake are controlled. One hypothesis is that there are sleep-inducing substances that accumulate during waking hours and then reach a certain tipping point that causes sleep. However, such a sleep substance has not been identified. Genes regulating the cellular circadian clock are implicated but operate on too slow a time scale to explain wake – sleep and wake – sleep transitions. University of Tokyo professor Hiroki Ueda has accumulated evidence for a different mechanism of sleep regulation in which calcium functions as a master regulator by virtue of its effects on phosphorylation of ion channels that regulate neuronal excitability. In this episode I talk with Hiro about his elegant experiments that use cutting-edge technologies to manipulate calcium-regulated kinases (CaMKII alpha and beta) in forebrain neurons while quantifying sleep and wakefulness by continuous monitoring of breathing patterns. Hiro also talks about the development in his laboratory of next generation single-cell genetics and whole-brain single cell imaging technologies and their broad applications in neuroscience research.

LINKS Review articles https://www.sciencedirect.com/science... https://pmc.ncbi.nlm.nih.gov/articles...

Whole brain single-cell atlas of neural activity https://www.science.org/doi/10.1126/s...

Competition between kinases and phosphatases in sleep-wake cycles https://www.nature.com/articles/s4158...

In this episode I talk with Weill Cornell Medicine professor Tim Ryan about the local regulation of energy metabolism in synapses. Tim and his colleagues use high resolution imaging of fluorescent probes that enable measurements of ATP and calcium in presynaptic terminals and postsynaptic dendrites of neurons in which energy substrates are manipulated. His lab has made several novel findings that refute previous assumptions concerning energy metabolism in neurons. Examples, include that neurons can store glycogen and triglycerides, and that free fatty acids and the ketone beta-hydroxybutyrate can fuel synapses and support neurotransmission. We also talk about gaps in understanding of the mechanistic links between calcium influx and energy metabolism in synapses, and the involvement of impaired synaptic energy metabolism in aging and neurodegenerative disorders.

LINKS

Tim Ryan laboratory page: https://sites.google.com/site/ryanlab1/Home

Articles

https://pmc.ncbi.nlm.nih.gov/articles/PMC5675126/pdf/nihms882178.pdf

https://pmc.ncbi.nlm.nih.gov/articles/PMC12286841/pdf/42255_2025_Article_1321.pdf

https://pmc.ncbi.nlm.nih.gov/articles/PMC11185772/pdf/nihpp-2024.06.08.598077v1.pdf

https://pmc.ncbi.nlm.nih.gov/articles/PMC12718339/pdf/pnas.202523019.pdf

In Alzheimer's disease and other 'Tauopathies' the Tau protein (which normally controls the polymerization of microtubules) becomes hyperphosphorylated and self-aggregates into insoluble fibrils called 'neurofibrillary tangles' within neurons. Excessive phosphorylation of Tau by a kinase called GSK3 is implicated in neurofibrillary tangle formation and neuron death in Alzheimer's disease. The Spanish biochemists Felix Hernandez and Jesus Avila made seminal discoveries concerning Tau tangle chemistry. In this episode I talk with Felix about that work and its importance for understanding, preventing, and treating Tauopathies. Interestingly, lithium (the third element on the periodic table) has long been known to be an effective treatment for bipolar disorder and more than 20 years ago Felix and his colleagues showed that lithium treatment prevents tau hyperphosphorylation and neurofibrillary tangle formation in a mouse model of frontotemporal dementia. Very recent findings from another laboratory suggest that low levels of lithium in the brain may be a risk factor for Alzheimer's disease. Clinical trials of lithium for tauopathy patients in the early stages of the disease are in progress.

LINKS

Felix and Jesus laboratory website:

https://www.cbm.uam.es/index.php/scientific-programs/physiological-and-pathological-processes/molecular-neuropathology/tau-function-and-dysfunction-in-alzheimer-disease/

Key articles

https://pmc.ncbi.nlm.nih.gov/articles/PMC140191/pdf/cde013.pdf

https://pubmed.ncbi.nlm.nih.gov/17059563/

https://pubmed.ncbi.nlm.nih.gov/14624025/

https://pubmed.ncbi.nlm.nih.gov/40770094/