The brain is not mental! coupling neuronal and immune cellular processing in human organisms
We next discuss the idea that neuronal processing in self-organizing biological systems such as the human body is intricately and dynamically linked to non-neuronal processing. Given space limitations, we restrict focus on the immune system only, but the same claim arguably holds for other non-neuronal cellular networks constituting the human body.
All cells of the organism originate from a single cell, the zygote, are closely interconnected, mutually influence one another, and operate in synchrony to achieve common goals–maintenance of homeostasis and constant adaptation to changes of the surrounding environment. In what follows, we depict cognitive processes carried out by non-neural cells, with a particular emphasis on the immune system.
Traditionally, the immune system is described as comprising two parts: the innate and adaptive immune systems. The innate immune system serves as the first line of defense, providing a rapid, non-specific response to pathogens, while the adaptive immune system can be trained to recognize and target specific antigens. However, this classification no longer fully encompasses our current understanding of the immune system. The immune system is a cellular network capable of distinguishing between self, non-self, missing-self, and aberrant-self, including misplaced cells and aberrant intracellular and extracellular molecules (Takeuchi and Akira, 2010; Coers, 2013; Iwasaki and Medzhitov, 2015; Di Virgilio et al., 2020; Zindel and Kubes, 2020). Functions of the immune system include detection, recognition, and elimination of pathogens, foreign substances, cancer cells, or damaged cells. It also plays a key role in inflammation, tissue repair, tissue remodeling, and regulation of immune response magnitude. A properly functioning immune system maintains a balance between responding to harmful and tolerating harmless agents or, in some cases, even tolerating harmful agents (Medzhitov, 2008; Medzhitov et al., 2012). In addition to classical immune functions, the immune system also regulates the nervous system, behavior, metabolism, thermogenesis, and participates in the fight-or-flight response (Dantzer et al., 2008; Rankin and Artis, 2018; Medzhitov, 2021).
The immune network encompasses dozens of distinct immune cell subsets, which communicate with each other and other cells through various means, including cytokines (interleukins, interferons, tumor necrosis factors), chemokines (chemotactic cytokines), various receptors, cell-to-cell interactions (immunological synapses, gap junctions), exosomes and macrovesicles, the complement system, hormones, and neuronal signaling. Along with the ability to interact at a distance by utilizing different molecules, immune cells are motile and can enter and exit the vascular system. As a result, they can migrate across various tissues and organs, which facilitates the coordination of immune processes and immune functions throughout the entire body. A key aspect of this system is the integration of diverse physiological information across distance in the organism, toward an adaptive response in a variety of changing conditions. Consistent with its role as an example of basal cognition, the immune system has been modeled as performing pattern recognition and classification (Carter, 2000).
The human immune system is thus composed of a complex network of numerous specialized cells distributed across the body (Rieckmann et al., 2017; Shilts et al., 2022). Complex arrays and maps of cell-surface proteins coordinate immune cells into inter-connected hubs, linking individual cells through physical interactions (Bergthaler and Menche, 2017). Remarkably, despite being composed of highly dynamic cell types constantly migrating throughout the body, the immune system is designed to flexibly organize its intercellular connections to respond to potential threats to the whole organism.
Importantly, the functional anatomy of the immune system is a key factor in the immune response. The body configuration matters as well as the spatial encapsulation of cells, necessary to spatially organize their chemical components in a such a way that time and place of molecular interactions are a necessary element of their effect (Farnsworth et al., 2013). These interactions are key for both intercellular signal communication and structural cohesion, holding literally the network together, and enabling successful tracking of self-not-self processing (Bausch-Fluck et al., 2018).
It has been proposed that the functions of the immune system are more complex than commonly thought, going beyond the self-not-self discrimination (Cohen and Efroni, 2019). In addition to shielding the body from pathogen, the immune network welcomes and orchestrates complex inflammatory responses designed to sustain the body and its symbiosis with fundamental bacterial microbiome and viral components. It also detects for example aged self-cells and destroys them, and rejects transplanted elements from allogeneic individuals (Cohen and Efroni, 2019).
It is also important to note that the innate immune response is not solely the property of specialized immune cells. Epithelial cells, endothelial cells, and fibroblasts also express various types of pattern-recognition receptors that detect pathogen-associated molecular patterns (associated with foreign agents) and damage-associated molecular patterns (originating from the host’s own stressed, injured, or dying cells) (Yirmiya and Goshen, 2011; Franz and Kagan, 2017). Furthermore, numerous non-immune cell types are able to sense nucleic acids and secrete type-I interferons in response to foreign nucleic acids in their cytoplasm (Schlee and Hartmann, 2016). Therefore, non-immune cells participate in the early stages of the immune response by secreting antimicrobial peptides, pro-inflammatory cytokines, and chemokines (Gallo and Hooper, 2012; Turner et al., 2014), that alert, recruit and activate immune cells, thereby initiating the cascade of immune response.
Tissue-resident immune cells, along with some non-immune cells, implement tissue immune surveillance by continuously monitoring and receiving signals from their environment. When a threat is identified, tissue-resident immune cells attempt to resolve the issue. If the problem persists, the danger alarm spreads, leading to the recruitment of additional immune cells from distant areas of the tissue and vasculature. The escalation continues if the threat remains. The magnitude of the immune response might reach a point where it induces behavioral changes known as “sickness behavior”: anorexia, emotional disturbances, social withdrawal, anhedonia and cognitive impairment. Sickness behavior is triggered by systemic pro-inflammatory cytokines secreted by immune cells (Herz and Kipnis, 2016; Kipnis, 2016; Rankin and Artis, 2018). To prevent detrimental excessive immune responses, the immune network regulates itself to balance immune activation and suppression through a negative feedback loop (production of anti-inflammatory cytokines), specialized regulatory cells (suppressing immune response through direct cell-cell contact or secretion of anti-inflammatory cytokines), expression of immune checkpoint molecules on the immune cell surface, apoptosis, and other mechanisms (Opal and DePalo, 2000; Strasser et al., 2009; Josefowicz et al., 2012; Pardoll, 2012; Nagata and Tanaka, 2017).
An essential feature of the immune system is its ability to acquire memory–a key property of cognitive systems. This process occurs in both the innate and adaptive immune systems, leading to a more robust and rapid response upon re-exposure to a stimulus (Netea et al., 2011, 2020; Kurosaki et al., 2015). In addition to immune memory to antigen, adaptive immune cells undergo “training” during their development and maturation—a process called “selection.” During selection, cells that can recognize various antigens without exhibiting self-reactivity are chosen for survival and continue to mature, while those that do not meet these criteria are eliminated through apoptosis. The purpose of selection is to ensure that the adaptive immune system can mount an effective immune response against foreign antigens without harming its own tissues (Nemazee, 2006; Klein et al., 2014). The innate immune system also has examples of “training” for functional competence and self-tolerance (Jentho and Weis, 2021). For instance, natural killer (NK) cells, a population of innate immune cells, undergo a process called “NK licensing” or “NK cell education” during their development. During the licensing process, immature NK cells are tuned for responsiveness, resulting in the generation of licensed or unlicensed NK cells. Licensed NK cells are more functionally competent and responsive compared to unlicensed NK cells; however, both subpopulations are important parts of the immune system (Kim et al., 2005; Orr and Lanier, 2010; Tu et al., 2016).
The described characteristics of the immune network are aligned with cognitive processes such as perception, attention, decision-making, communication, problem-solving, learning, and memory. As previously mentioned, the immune system heavily communicates, interacts, and regulates (and is regulated by) other systems of the body (Eskandari et al., 2003; Hu and Pasare, 2013; Fleshner and Crane, 2017). The immune system, along with the neural and endocrine systems, are considered the major control systems in organisms, tightly linked to one another. Neurons create their own networks by connecting directly to each other via synapses, enabling rapid communication and quick information processing. In contrast, the endocrine and immune systems utilize the cardiovascular and lymphatic systems for distant communication. These three systems are closely connected, essentially forming a single network for information processing and action (Besedovsky and Rey, 2007; Dantzer et al., 2008; Dantzer, 2018). For instance, acute stress induced by physical and psychological conditions leads to the secretion of neurotransmitters and hormones such as corticotropin-releasing hormone, vasopressin, vasoactive intestinal polypeptide, serotonin, beta-endorphins, neuropeptide Y, adrenocorticotropic hormone, glucocorticosteroids, norepinephrine, and epinephrine (Black and Garbutt, 2002; Dhabhar et al., 2012; Weigent, 2013). Immune cells express receptors for glucocorticoids and catecholamines (α and β2-adrenoreceptors), enabling the immune network to perceive, pay attention to, and react to stress signals (Kohm and Sanders, 2000; Pavlov and Tracey, 2005; Drummond, 2014; Wohleb et al., 2015).
In response to acute stress, some subsets of immune cells exit their depos into blood circulation and migrate to the barrier tissues, such as skin, in order to combat microorganisms in the event of skin damage (e.g., scratches or bites) (Schedlowski et al., 1993; Dimitrov et al., 2009; Dhabhar et al., 2012).
Interestingly, immune cells can be a source of peptide hormones and neurotransmitters such as acetylcholine, adrenocorticotropic hormone, endorphins, enkephalins, vasoactive intestinal peptide, substance P, vasopressin, atrial natriuretic peptide, and corticotropin-releasing hormone (Blalock, 2005; Blalock and Smith, 2007). Furthermore, cytokines produced by immune cells regulate neuronal function, influence brain development, and behavioral abnormalities (Yirmiya and Goshen, 2011; Bilbo and Schwarz, 2012; Choi et al., 2016; Kim et al., 2017). Moreover, the immune network can impact cognitive function through the modulation of pain (McMahon et al., 2005; Ren and Torres, 2009; Moriarty et al., 2011; Grace et al., 2014; Gupta and Harvima, 2018) or by involvement in the gut-brain axis (Sharon et al., 2016; Strandwitz, 2018).
An extensive and systematic review of the mechanisms enabling immune cells to dynamically wire their circuits and interactions throughout the body is outside the scope of this paper (see Rieckmann et al., 2017; Cohen and Efroni, 2019; Shilts et al., 2022 for a recent discussion). In what follows we focus on the brain-immune cellular networks relationship.
The immune system is uniquely like the brain: both brain and immune system develop fully, far beyond their genes, as a result of somatic lifetime experience (Cohen, 2000). Under the hierarchical perspective of the FEP, it has been argued that the brain and the immune system are internal states of the same Markov blanket and necessarily influence each other (Palacios et al., 2020; Bhat et al., 2021). Markov blankets are typically defined as a statistical boundary that separates two sets of states (e.g., a cellular membrane separating intracellular and extracellular dynamics) (Pearl, 1988; see Bruineberg et al., 2021 for a critical discussion).
Recent work by Schwartz et al. (2022) proposed the idea of a brain-immune network “ecosystem.” The received view considered indeed the brain as a self-contained tissue responsible for its own immune protection and equipped with microglia, acting as internal immune sentinels. However, as Shechter et al. (2013) note, the Central Nervous System (CNS) repair and higher brain function (Ziv et al., 2006) have been found to be dependent on adaptive and innate immune cells derived from the circulation. These findings opened the search for regions within the brain containing adaptive immune cells which are considered able to affect the brain from distance. Intriguingly, the discovery of border structures through which reparative immune cells can enter the brain to provide help without breaching the blood-brain barrier (Shechter et al., 2013) open a new window into the complex relationship between the CNS and the immune networks.
The brain-immune network “ecosystem” consists of the idea that “the cellular elements of this immunological network, together with the non-immune cells of the brain—neurons, astrocytes, and oligodendrocytes—constitute a functional structure with properties of an “ecosystem,” characterized by interdependent compartments of immune cells that interact with each other within a physically connected microenvironment, thereby contributing to increased stability and resilience of the CNS in the face of continuous disruption in its day-to- day activities.” [Schwartz et al. (2022):1].
It is also important to stress that the human brain is not composed of neurons only, but also of non-neuronal cell types. The latter may have a lower diversity than neurons in baseline adult state. Yet many non-neuronal cell types undergo significant changes, i.e., they exhibit many different cell states, under different physiological or diseased situations (Zeng, 2022). For example, astrocytes display complex morphological and physiological properties in different brain regions and contribute to essential functions in blood-brain barrier, synaptogenesis, neurotransmitter buffering, ion homeostasis, and secretion of neuroactive agents (Ben Haim and Rowitch, 2017).
Crucially, the cells called microglia are the primary innate immune cells in the central nervous system and have a distinct developmental origin from peripheral immune cells (Thion and Garel, 2020). They are generated from mesodermal progenitors that arise from the yolk sac and remarkably, they are among the earliest residential cell types in the brain. Microglia display diverse and dynamic phenotypic states and play a plethora of roles in development, adulthood (homeostasis), aging, and diseases (Butovsky and Weiner, 2018).
Based on the observation that immunity is not merely an automatic response to a foreign presence, it has been proposed to characterize immune processing as an “act of cognition” (Cohen, 1992). Since human bodies are biological self-organizing open systems, the development and function of a cellular network designed to keep track of the “self” in relation to both the external environment, and its internal structures may be seen indeed as an essential cognitive system. This system needs to be flexible and “smart” enough to decide on the fly whether certain elements are optimal for and/or belong or not to this self-organizing system. It also needs to compute whether certain self-organizing processes unfold according to the plan or go awry. Interestingly, this idea can be traced back to the seminal work of Varela and Coutinho (1991a),b; Varela et al. (1998) (see also Vaz, 2011) who paid careful attention to the special interplay between immune and somatic processes, coining the term “immunoknowledge” (Varela and Coutinho, 1991a).
One key observation is that taken in isolation, when confronted with a pathogen or incoming signal, each individual immune cell has a limited “view.” An individual cell is blind to information that does not directly activate its reception. To put it metaphorically: “each cell is confined to a world compressed by its own short-sightedness (Cohen and Efroni, 2019:3). Hence, in order to ensure flexible response to pathogens and other incoming signals, individual immune cells must coordinate and integrate their disparate responses to produce a systemic decision. Based on this observation, it has been proposed that the network of immune cells make “collective decisions through a type of self-organizing swarm intelligence or crowd wisdom “(Cohen and Efroni, 2019:1). This idea is in line with previous work showing that the collective coordinated behavior of cells composing an organ or a tissue requires information processing tracking the internal state of the neighboring cells (Perbal, 2003). It has been shown that the iterative exchange of information involving cell-to-cell communication may give rise to cooperative cellular behavior even under noisy conditions (Koseska et al., 2009).
In a similar vein and taking this line of reasoning one step further, one may argue that neuronal cells also, taken in isolation, may be equally blind to which type of information is noteworthy for optimal responsiveness and processing of key physiological states of the self-organizing biological system it supervises as a whole–the human body. The same way immune cells interact and communicate with each other to deliver flexible response to incoming signals, the neuronal cells need to interact not only with each other, but also with non-neuronal cells (e.g., immune cells) to coordinate joint responses. Collective teamwork of neuronal and immune signaling need to constantly orchestrate on the fly joint finetuned responses to meet constantly changing incoming signals from the body and the environment.
Moreover, not only individual cells, but also specialized organs and networks may equally have a limited “short-sighted” view of the world of the organism it composes and ensure self-preservation. Hence one may speculate that biological self-organization in the human body emerges as a “crowd wisdom” not only at the inter-cellular level subserving a given network (neural, immune, endocrinologic, etc.). Importantly, it emerges also at the inter-networks level, that is, from the interactions between different systems orchestrating their responses in tandem to address key challenges for the survival of the body. Given that biological organisms are fundamentally multi-scale evolving agents, cognitive processing should equally display a multi-scale distributed structure, with the immune system playing a central, yet overlooked role, working in tandem with the neural system (Varela and Coutinho, 1991a,b).
It is important to stress here that the aim here is not to provide an explanation to the perennial mind-body problem, i.e., how mental states emerge from physical states in the brain. The aim rather is to point out that the very distinction between mind and body, inherited from previous traditions, tacitly confines cognitive processing to the brain only. However, if cognition is defined as information processing, then all bodily cells are cognitive in this minimal sense, not just those operating in the brain.2
Up to now we have overviewed theoretical and empirical work suggesting that self-organizing biological systems such as human bodies are structured by complex sets of dynamically reciprocal pathways in which each neuron/cell both shapes and are shaped by the organism’s regulatory and developmental processes as a whole. In the last section, we take a closer look at the idea that cognitive processing is best described as an intricate interplay between both macro- and microscopic processing at hierarchical multisystem levels distributed across the whole organism.
Taken together, this robust body of evidence reviewed above points to the idea that cognition can be seen as a multiscale complex web of dynamic information processing distributed across multilevel cellular (e.g., neural and immune) and network systems operating across the entire body, and not just in the brain.
Prevailing approaches in cognitive neuroscience tacitly stipulate that brain states are somehow the natural, necessary home of cognitive information processing.
Yet, “smart” information processing seems to be pervasive at the non-neuronal cellular level as well. If this is so, then one may ask why cognitive and by extrapolation mental processes are so tenaciously associated with brain and neuronal processes only. This is an important and complex question that calls for careful and systematic consideration in future work. However, here we briefly list what we take to be some key elements supporting the tacit privilege of neurons over other type of cells in constituting cognition.
First, cognition has been examined preferentially from an adult-centric static approach, focusing on the brain as fully developed organ. However, it has been recently argued in favor of a developmental turn in understanding how brains and neurons emerge in relation to the rest of the other bodily organs and others’ bodies throughout the lifespan (Blakemore, 2012; Ciaunica and Fotopoulou, 2017; Ciaunica et al., 2021a,b). This dynamic approach may open new windows exploring how perception, cognition and self-processing temporally evolve from the womb into early infancy and beyond (Ciaunica and Crucianelli, 2019). Recent work has outlined that the boundaries between neuronal and non-neuronal cellular processing are much more complex and malleable than has been appreciated. This holds especially when one endorses a dynamic, developmental perspective on the growing brain and organism, tracing multi-layered cognition spanning from basic, cellular levels to higher psychological levels (Herrera-Rincon and Levin, 2018; Ciaunica et al., 2021a,b; Lyon et al., 2021).
For example, the transformation from unicellular to complex multicellular organisms requires the multiplication of the individual cells and the diversification of their function across the lifespan. The entire human repertoire of brain and body cell types are built, as Zeng notes, “through a sequential and parallel series of spatially and temporally coordinated developmental events starting from a single fertilized egg, the zygote” (Zeng, 2022:2748). The observation that cell type development is not a simple linear process but a highly multifaceted one invites us to reconsider the classical picture of a “pyramidal” hierarchical cell organization. Rather, a “tree of cell types” (Zeng, 2022: 2750) may be a more accurate picture for capturing the overarching classification of cell types and their complex relationships (Stadler et al., 2021).