Learning to become addicted, one synapse at a time
Year: 2023
Type: article
Abstract: Addiction has been extensively studied on many levels: from the molecular level, with various “omics” approaches (Natividad et al., 2018; Grecco et al., 2021), to the clinical level, with psychotherapy and MRI imaging (Ceceli et al., 2022). These approaches have identified brain regions central to addictive processes and reward behavior such as the nucleus accumbens (NA) and the ventral tegmental area. Particularly, the NA exhibits significant volume changes as a consequence of chronic alcohol, heroin, or cigarette abuse as measured by voxel-based morphometry with magnetic resonance imaging in human patients. However, the underlying cellular basis for such large-scale changes is not well understood. Studies in animal models suggest that cellular correlates of volume changes are dependent on alterations in spine/synapse densities and synapse volumes, rather than cell numbers (Keifer et al., 2015). In the NA, substantial spine loss on medium spiny neurons occurs upon withdrawal from various substances of abuse, including alcohol and cocaine (Spiga et al., 2014). Loss of spines is also likely accompanied by a loss of presynaptic boutons; additionally, regional alterations in dendritic arborization could also play a substantial role in the volume changes. While some of these changes may arise as secondary downstream effects due to toxicity after extended substance abuse, morphological changes are beginning to emerge as an important mediator of the effects of substances of abuse on the brain (Russo et al., 2010). Recently, Knabbe et al. (2022) found increased spine turnover and bouton loss in neocortical neurons of somatosensory and motor areas in live mice following a single ethanol administration. This study thus showed that drug-induced morphological changes can occur in brain areas not directly associated with drug-related behavior. If and how such observed morphological changes are critical to the development of addiction is not clear. In the following, we discuss how morphological plasticity processes akin to learning could lead to addiction. The plasticity and dynamics of neuronal morphology and its relationship to physiological learning and memory have been intensely researched during the last two decades. Morphological plasticity is at the core of brain function as it supports functional connectivity and development of neuronal networks and their homeostasis. The structural functional plasticity of synapses is posited to underlie the ability of brains to learn and recall information. For example, long-term potentiation, the process considered to be the basis of learning and memory, robustly leads to spine growth (Engert and Bonhoeffer, 1999) and increases in spine head size. Long-term potentiation can be induced with a single tetanic electrophysiological stimulus and the resulting potentiation of synaptic transmission is considered a physiological memory correlate that lasts beyond the inducing stimulus up to a few hours. During the last decade, these fundamental memory correlates and the molecular changes underlying them (Luscher and Malenka, 2011) have been increasingly implicated in the development and maintenance of addiction. While it seems obvious that positive reward memories of addiction are based on the same neuronal substrates as other memories, the identification of a lasting cellular addictive memory correlate following an acute substance stimulus has been lacking. Based on quantitative synaptic proteome analyses following an acute ethanol administration, Knabbe et al. (2022) identified lasting molecular changes related to neuronal morphology and mitochondria. Remarkably, changes in synapse morphology, axonal initial segment lengths, and mitochondria trafficking lasted significantly longer than a single ethanol stimulus in alcohol-naïve mice. Because of the high ethanol metabolism in mice, ethanol is fully metabolized within 3–4 hours after injection. Using in vivo two-photon imaging, the authors detected an increase in presynaptic bouton loss 24 hours after an acute ethanol injection; this phenomenon was more prominent in boutons without mitochondria. Post-synaptically, the authors reported an increase in spine turnover following a one-time exposure to ethanol in addition to a decrease in the length of the axon initial segment. Also, 4 hours after ethanol injection, the extent of mitochondrial trafficking in cortical axons roughly doubled in comparison to control mice. Collectively, the observed lasting changes, i.e., morphological alterations in synapses and the axonal initial segment together with the increased mitochondrial trafficking, constitute possible cellular correlates of the memory processes underlying addiction. Knabbe et al. (2022) demonstrated the importance of these cellular correlates for the development of addiction and positive reward memories by interfering with trafficking of mitochondria in the fruit fly Drosophila and finding that impaired mitochondrial trafficking completely abolished alcohol-associated odor preference. As the influence of ethanol on mitochondrial trafficking appears conserved across species, these findings strongly indicate that mitochondrial dynamics could indeed be an important lasting, neuronal substrate of addictive memories. Importantly, in mice, the impaired mitochondrial trafficking in axons upon a single exposure to alcohol was found in neurons of cortical areas M1/S1, which have not been related to alcohol-induced behavioral activities, thereby implying a general effect of ethanol on different neuronal classes in addition to neurons in the NA or ventral tegmental area. Since studies of cellular learning and memory mechanisms are typically conducted with neocortical neurons and because Knabbe et al. found ethanol-related changes in neocortical neurons, it is thus conceivable that higher cortical forebrain areas could be more involved in addictive behavior than currently assumed. Not surprisingly, besides ethanol, also other substances of abuse and anesthetics were found to induce substantial changes in cortical spine/synapse density upon single exposures. Ketamine and isoflurane both affect synaptic glutamate signaling (as does ethanol) and so the ensuing morphological changes following exposure to these compounds could possibly be another indicator for the involvement of synaptic connectivity changes in addictive behavior. Knabbe et al. (2022) described widespread morphological changes in neurons after a single exposure to ethanol. Unlike chronic alcohol treatments, these experimental efforts thus allowed a first look at the earliest stages of addiction development. For addiction to manifest itself from sporadic episodes, lasting changes need to endure in the brain to bridge isolated substance consumption events on a cellular level (Figure 1). The substance of abuse-related morphological changes as demonstrated by Knabbe et al. (2022), including the increased disappearance of pre-existing and the formation of new synapses, certainly exhibit the necessary temporal endurance and the necessary functional impact to shift neuronal circuitry and behavior. Structural synaptic dynamics, in fact, have been causally associated with learning and recall across various brain areas and behavioral paradigms in rodents. For instance, in motor cortical areas, survival of dendritic spines showed a positive correlation with the ability of mice to perform motor tasks and, conversely, interfering with the potentiation of dendritic spines upon learning a motor task led to a decrease in performance specifically in that motor task. In addition, it has recently been demonstrated that learning involves not only the potentiation of task-related spines but also the strengthening of the task-related network by recruiting additional axons of presynaptic neurons (Hedrick et al., 2022). Similar correlations between dendritic spine dynamics and overall information acquisition and storage have been demonstrated in the visual, barrel, auditory, and retrosplenial cortices as well as the dorsal hippocampal CA1 region. Thus, it would be surprising for addiction memories to not rely on morphological plasticity. To further our understanding of how sporadic consumption can lead to addiction, we, therefore, believe it is crucial to continue identifying morphological changes following a one-time stimulus, not only in alcohol research but in all fields of addictive substance research. We posit that, from one stimulus to the next, there could be an additive set of successive morphological changes “one synapse at a time” that will eventually manifest itself in a full-blown addiction. Support for this hypothesis comes also from research on imprinting. Imprinting has most famously been described for newborn chicks to learn which subject to follow when leaving the nest, showing that a single event/stimulus can lead to lasting changes with substantial functional consequences at further time points. Similarly, monocular deprivation during a critical period in mice has been shown to change the structure of excitatory and inhibitory networks in the primary visual cortex leading to re-arrangements that can prime the network to respond to further episodes of monocular deprivation (Hofer et al., 2009). Thus, imprinting processes critically depend on morphological plasticity processes based on dynamic synaptic changes and highlight the possibility of lasting cognitive alterations following a single event. We wonder if the ethanol-mediated, lasting morphological changes described by Knabbe et al., (2022) can be assimilated to an imprinting-like process with the first exposure to alcohol generating changes that will influence future behavior by affecting the way the network will respond to future exposures to alcohol. Subsequent exposures could successively strengthen network connectivity, akin to learning a task with initial exposures having a larger impact compared to later ones (Figure 1). Although the temporal windows of critical periods in humans are scattered across the first twenty years of life or so for different tasks and are much less well-defined compared to those in animal models, the development of addiction may still be comparable to an imprinting process. In fact, it is established that teenagers are at high risk for the development of addiction and earlier exposure to ethanol during adolescence leads to a higher probability of alcohol abuse later in life (DeWit et al., 2000). The cellular mechanisms underlying these processes are not understood but it is well established that neuronal plasticity is generally more profound in younger than older individuals (Figure 1) and it is every adult’s personal experience that it is more difficult to learn a new task later compared to earlier in life. Thus, ethanol exposure at a younger age might induce “learning” with more profound morphological changes upon which downstream addiction can manifest itself more easily and more robustly. In light of the dire consequences for individuals and for our society, we hope that recent and future research can contribute to a better understanding of serious addictions and their development. We propose to de-emphasize the focus on brain regions known to be important for addiction to a focus on networks important for learning and memory which are distributed across the entire brain. To this aim, we now have at our disposal very powerful research tools such as in vivo two-photon microscopy for high-resolution imaging of synaptic morphology and dynamics. Longitudinal imaging of networks before, during, and after acute exposure to substances of abuse will undoubtedly elevate our understanding of how cellular memory processes and morphological plasticity of synapses contribute to the development of addiction. We highlighted here parallels between addiction and normal learning processes and we hope that the integration of both in future research will eventually provide better coping strategies for dealing with addiction.Figure 1: The contribution of morphological plasticity to addiction development.Given the higher intrinsic structural plasticity during adolescence, substance-related plasticity events possibly have a more potent effect on structural changes of the neuronal network. This in turn elevates the chances of neuronal networks reaching a threshold to drive addiction. Created with Microsoft PowerPoint.C-Editors: Zhao M, Liu WJ, Qiu Y; T-Editor: Jia Y
Source: Neural Regeneration Research
Authors: Alessio Attardo, Sidney B. Cambridge
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $1,500
OpenAlex ID: W4384830076