Aging as a Consequence of the Adaptation-Maladaptation Dilemma.

In aging, the organism is unable to counteract certain harmful influences over its lifetime which leads to progressive dysfunction and eventually death, thus delineating aging as one failed process of adaptation to a set of aging stimuli. A central problem in understanding aging is hence to explain why the organism cannot adapt to these aging stimuli. The adaptation-maladaptation theory of aging proposes that in aging adaptation processes such as adaptive transcription, epigenetic remodeling, and metabolic plasticity drive dysfunction themselves over time (maladaptation) and thereby cause aging-related disorders such as cancer and metabolic dysregulation. The central dilemma of aging is thus that the set of adaptation mechanisms that the body uses to deal with internal and external stressors acts as a stressor itself and cannot be effectively counteracted. The only available option for the organism to decrease maladaptation may be a program to progressively reduce the output of adaptive cascades (e.g., via genomic methylation) which then leads to reduced physiological adaptation capacity and syndromes like frailty, immunosenescence, and cognitive decline. The adaptation-maladaptation dilemma of aging entails that certain biological mechanisms can simultaneously protect against aging as well as drive aging. The key to longevity may lie in uncoupling adaptation from maladaptation.

Aging, adaptation and maladaptation.

Aging is accompanied by a dysregulation of adaptive processes. On the one hand, physiological adaptation mechanisms such as learning and memory, immune system plasticity and exercise-dependent muscle remodeling are blunted. On the other hand, several maladaptive processes increase with age including cancer, pathological cardiovascular remodeling and metabolic dysregulation. With increasing age the quotient of beneficial adaptation (Ab) to harmful adaptation (Ah), Ab/Ah, decreases. The adaptation-maladaptation framework of aging entails that there are age-related pathological phenotypes that are the result of activation of physiological adaptation mechanisms (e.g., maladaptation as a result of misdirection of adaptive cascades and molecular damage incurred by adaptation processes) and their occurrence over time might, to some degree, be inevitable. Aging might hence result from the organism's inability to solve the adaptation-maladaptation dilemma. The present work explores the concept of counteracting aging through adaptation and proposes that interventions such as exercise, environmental enrichment and dietary restriction work in counteracting aging because they increase the ratio Ab/Ah by both raising Ab (e.g., by inducing metaplasticity in cells, meaning they raise the adaptability of cells to future stimuli) and decreasing Ah (e.g., through desensitizing certain potentially harmful adaptive mechanisms). Molecules whose aging-related expression changes can explain aspects of dysfunctional adaptation such as CREB and certain immediate early genes are examined and it is delineated how a better understanding of the dynamical organization of adaptation cascades could elucidate the seemingly complex role of adaptation in driving aging as well as protecting against it.

Activity-Dependent Induction of Younger Biological Phenotypes.

In several mammalian species, including humans, complex stimulation patterns such as cognitive and physical exercise lead to improvements in organ function, organism health and performance, as well as possibly longer lifespans. A framework is introduced here in which activity-dependent transcriptional programs, induced by these environmental stimuli, move somatic cells such as neurons and muscle cells toward a state that resembles younger cells to allow remodeling and adaptation of the organism. This cellular adaptation program targets several process classes that are heavily implicated in aging, such as mitochondrial metabolism, cell-cell communication, and epigenetic information processing, and leads to functional improvements in these areas. The activity-dependent gene program (ADGP) can be seen as a natural, endogenous cellular reprogramming mechanism that provides deep insight into the principles of inducible improvements in cell and organism function and can guide the development of therapeutic approaches for longevity. Here, these ADGPs are analyzed, exemplary critical molecular nexus points such as cAMP response element-binding protein, myocyte enhancer factor 2, serum response factor, and c-Fos are identified, and it is explored how one may leverage them to prevent, attenuate, and reverse human aging-related decline of body function.

Npas4 regulates medium spiny neuron physiology and gates cocaine-induced hyperlocomotion.

We show here that the transcription factor Npas4 is an important regulator of medium spiny neuron spine density and electrophysiological parameters and that it determines the magnitude of cocaine-induced hyperlocomotion in mice. Npas4 is induced by synaptic stimuli that cause calcium influx, but not dopaminergic or PKA-stimulating input, in mouse medium spiny neurons and human iPSC-derived forebrain organoids. This induction is independent of ubiquitous kinase pathways such as PKA and MAPK cascades, and instead depends on calcineurin and nuclear calcium signalling. Npas4 controls a large regulon containing transcripts for synaptic molecules, such as NMDA receptors and VDCC subunits, and determines in vivo MSN spine density, firing rate, I/O gain function and paired-pulse facilitation. These functions at the molecular and cellular levels control the locomotor response to drugs of abuse, as Npas4 knockdown in the nucleus accumbens decreases hyperlocomotion in response to cocaine in male mice while leaving basal locomotor behaviour unchanged.

Dnmt3a2 in the Nucleus Accumbens Shell Is Required for Reinstatement of Cocaine Seeking.

Epigenetic mechanisms have gained increasing attention as regulators of synaptic plasticity and responsiveness to drugs of abuse. In particular, it has been shown that the activity of the DNA methyltransferase 3a (Dnmt3a) mediates certain long-lasting effects of cocaine. Here we examined the role of the Dnmt isoforms, Dnmt3a1 and Dnmt3a2, within the nucleus accumbens (NAc) on transcriptional activity of immediate early genes (IEGs) and acute and long-lasting responsiveness to cocaine and cocaine conditioned cues. Using primary striatal cultures, we show that transcription of Dnmt3a2, but not that of Dnmt3a1, is activated by dopamine D1 receptor signaling and that knockdown of Dnmt3a2 using viral vector-mediated expression of Dnmt3a2-specific shRNAs impairs induction of the IEGs, Arc, FosB, and Egr2 Acute cocaine administration increases expression of Dnmt3a2 but not that of Dnmt3a1 in the NAc shell. In contrast, in the NAc core, expression of Dnmt3a1 and Dnmt3a2 was unaffected by cocaine administration. shRNA-mediated knockdown of Dnmt3a2 in vivo impairs the induction of IEGs, including Egr2 and FosB indicating that Dnmt3a2 regulates cocaine-dependent expression of plasticity genes in the rat NAc shell. Cocaine self-administration experiments in rats revealed that Dnmt3a2 regulates drug cue memories that drive reinstatement of cocaine seeking as well as incubation of this phenomenon within the NAc shell. Dnmt3a2 does not influence the primary reinforcing effects of cocaine. Thus, Dnmt3a2 mediates long-lasting cocaine cue memories within the NAc shell. Targeting Dnmt3a2 expression or function may interfere with cocaine craving and relapse.SIGNIFICANCE STATEMENT In humans, drug craving can occur in response to conditioned cues, even after extended periods of abstinence. In rats, cue-induced cocaine seeking has been shown to increase progressively during the first 2 months of abstinence from drug self-administration. This phenomenon, referred to as incubation of cocaine seeking, is consistent with the hypothesis that in humans craving increases over time and remains high following prolonged abstinence. Those long-lasting behavioral changes are likely to be mediated by epigenetic effects and neuroplastic changes within the mesolimbic brain reward system. Here we show that a specific isoform of DNA-methyltransferases in the NAc shell regulates drug cue memories that drive reinstatement of cocaine seeking after both early abstinence and incubation of cocaine craving.

Interfacing Neural Network Components and Nucleic Acids.

Translating neural activity into nucleic acid modifications in a controlled manner harbors unique advantages for basic neurobiology and bioengineering. It would allow for a new generation of biological computers that store output in ultra-compact and long-lived DNA and enable the investigation of animal nervous systems at unprecedented scales. Furthermore, by exploiting the ability of DNA to precisely influence neuronal activity and structure, it could be possible to more effectively create cellular therapy approaches for psychiatric diseases that are currently difficult to treat.

Building Bridges through Science.

Science is ideally suited to connect people from different cultures and thereby foster mutual understanding. To promote international life science collaboration, we have launched "The Science Bridge" initiative. Our current project focuses on partnership between Western and Middle Eastern neuroscience communities.

General Anesthetic Conditions Induce Network Synchrony and Disrupt Sensory Processing in the Cortex.

General anesthetics are commonly used in animal models to study how sensory signals are represented in the brain. Here, we used two-photon (2P) calcium activity imaging with cellular resolution to investigate how neuronal activity in layer 2/3 of the mouse barrel cortex is modified under the influence of different concentrations of chemically distinct general anesthetics. Our results show that a high isoflurane dose induces synchrony in local neuronal networks and these cortical activity patterns closely resemble those observed in EEG recordings under deep anesthesia. Moreover, ketamine and urethane also induced similar activity patterns. While investigating the effects of deep isoflurane anesthesia on whisker and auditory evoked responses in the barrel cortex, we found that dedicated spatial regions for sensory signal processing become disrupted. We propose that our isoflurane-2P imaging paradigm can serve as an attractive model system to dissect cellular and molecular mechanisms that induce the anesthetic state, and it might also provide important insight into sleep-like brain states and consciousness.