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In this paper we compare the strategies applied by two successful biological components of the ecosystem, the viruses and the human beings, to interact with the environment. Viruses have had and still exert deep and vast actions on the ecosystem especially at the genome level of most of its biotic components. We discuss on the importance of the human being as contraptions maker in particular of robots, hence of machines capable of automatically carrying out complex series of actions. Beside the relevance of designing and assembling these contraptions, it is of basic importance the goal for which they are assembled and future scenarios of their possible impact on the ecosystem. We can’t procrastinate the development and implementation of a highly inspired and stringent “ethical code” for human beings and humanoid robots because it will be a crucial aspect for the wellbeing of the mankind and of the entire ecosystem.

Background: Roles of astrocytes in the modulatory effects of oxytocin (OT) in central nervous system are increasingly considered. Nevertheless, OT effects on gliotransmitter release have been neglected. Methods: In purified astrocyte processes from adult rat striatum, we assessed OT receptor (OTR) and adenosine A2A receptor expression by confocal analysis. The effects of receptors activation on glutamate release from the processes were evaluated; A2A-OTR heteromerization was assessed by co-immunoprecipitation and PLA. Structure of the possible heterodimer of A2A and OT receptors was estimated by a bioinformatic approach. Results: Both A2A and OT receptors were expressed on the same astrocyte processes. Evidence for A2A-OTR receptor-receptor interaction was obtained by measuring the release of glutamate: OT inhibited the evoked glutamate release, while activation of A2A receptors, per se ineffective, abolished the OT effect. Biochemical and biophysical evidence for A2A-OTR heterodimers on striatal astrocytes was also obtained. The residues in the transmembrane domains 4 and 5 of both receptors are predicted to be mainly involved in the heteromerization. Conclusions: When considering effects of OT in striatum, modulation of glutamate release from the astrocyte processes and of glutamatergic synapse functioning, and the interaction with A2A receptors on the astrocyte processes should be taken into consideration.

In the last decades, new evidence on brain structure and function has been acquired by morphological investigations based on synergic interactions between biochemical anatomy approaches, new techniques in microscopy and brain imaging, and quantitative analysis of the obtained images. This effort produced an expanded view on brain architecture, illustrating the central nervous system as a huge network of cells and regions in which intercellular communication processes, involving not only neurons but also other cell populations, virtually determine all aspects of the integrative function performed by the system. The main features of these processes are described. They include the two basic modes of intercellular communication identified (i.e., wiring and volume transmission) and mechanisms modulating the intercellular signaling, such as cotransmission and allosteric receptor–receptor interactions. These features may also open new possibilities for the development of novel pharmacological approaches to address central nervous system diseases. This aspect, with a potential major impact on molecular medicine, will be also briefly discussed.

The ability of oxytocin (OT) to interact with the dopaminergic system through facilitatory D2-OT receptor (OTR) receptor-receptor interaction in the limbic system is increasingly considered to play roles in social or emotional behavior, and suggested to serve as a potential therapeutic target. Although roles of astrocytes in the modulatory effects of OT and dopamine in the central nervous system are well recognized, the possibility of D2-OTR receptor-receptor interaction in astrocytes has been neglected. In purified astrocyte processes from adult rat striatum, we assessed OTR and dopamine D2 receptor expression by confocal analysis. The effects of activation of these receptors were evaluated in the processes through a neurochemical study of glutamate release evoked by 4-aminopyridine; D2-OTR heteromerization was assessed by co-immunoprecipitation and proximity ligation assay (PLA). The structure of the possible D2-OTR heterodimer was estimated by a bioinformatic approach. We found that both D2 and OTR were expressed on the same astrocyte processes and controlled the release of glutamate, showing a facilitatory receptor-receptor interaction in the D2-OTR heteromers. Biochemical and biophysical evidence confirmed D2-OTR heterodimers on striatal astrocytes. The residues in the transmembrane domains four and five of both receptors are predicted to be mainly involved in the heteromerization. In conclusion, roles for astrocytic D2-OTR in the control of glutamatergic synapse functioning through modulation of astrocytic glutamate release should be taken into consideration when considering interactions between oxytocinergic and dopaminergic systems in striatum.

Background: Angiotensin-converting enzyme 2 (ACE2) is primarily involved in the maturation of angiotensin. It also represents the main receptor for the Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) that caused a serious epidemic COVID-19. Available evidence indicates that at the cell membrane, ACE2 can form heteromeric complexes with other membrane proteins, including the amino acid transporter B0 AT1 and G protein-coupled receptors (GPCR). Objective: It is well known that during the formation of quaternary structures, the configuration of every single monomer is re-shaped by its interaction pattern in the macromolecular complex. Therefore, it can be hypothesized that the affinity of ACE2 to the viral receptor-binding domain (RBD), when in a heteromeric complex, may depend on the associated partner. Methods: By using established docking and molecular dynamics procedures, the reshaping of monomer was explored in silico to predict possible heterodimeric structures between ACE2 and GPCR, such as angiotensin and bradykinin receptors. The associated possible changes in the binding affinity between the viral RBD and ACE2 when in the heteromeric complexes were also estimated. Results and Conclusion: The results provided support to the hypothesis that the heteromerization state of ACE2 may modulate its affinity to the viral RBD. If experimentally confirmed, ACE2 heteromerization may contribute to explain the observed differences in susceptibility to virus infection among individuals and to devise new therapeutic opportunities.

The discovery that receptors from all families can establish allosteric receptor–receptor interactions and variably associate to form receptor complexes operating as integrative input units endowed with a high functional and structural plasticity has expanded our understanding of intercellular communication. Regarding the nervous system, most research in the field has focused on neuronal populations and has led to the identification of many receptor complexes representing an important mechanism to fine-tune synaptic efficiency. Receptor–receptor interactions, however, also modulate glia–neuron and glia–glia intercellular communication, with significant consequences on synaptic activity and brain network plasticity. The research on this topic is probably still at the beginning and, here, available evidence will be reviewed and discussed. It may also be of potential interest from a pharmacological standpoint, opening the possibility to explore, inter alia, glia-based neuroprotective therapeutic strategies.

The discovery of receptor-receptor interactions in the early 1980s, together with a more accurate focusing of allosteric mechanisms in proteins, expanded the knowledge on the G protein-coupled receptor (GPCR)-mediated signaling processes. GPCRs were seen to operate not only as monomers, but also as quaternary structures shaped by allosteric interactions. These integrative mechanisms can change the function of the GPCRs involved, leading to a sophisticated dynamic of the receptor assembly in terms of modulation of recognition and signaling. In this context, the heterodimeric complex formed by the adenosine A

The discovery of receptor-receptor interactions in the early 1980s, together with a more accurate focusing of allosteric mechanisms in proteins, expanded the knowledge on the G protein-coupled receptor (GPCR)-mediated signaling processes. GPCRs were seen to operate not only as monomers, but also as quaternary structures shaped by allosteric interactions. These integrative mechanisms can change the function of the GPCRs involved, leading to a sophisticated dynamic of the receptor assembly in terms of modulation of recognition and signaling. In this context, the heterodimeric complex formed by the adenosine A2A and the dopamine D2 receptors likely represents a prototypical example. The pharmacological evidence obtained, together with the tissue distribution of the A2A-D2 heteromeric complexes, suggested they could represent a target for new therapeutic strategies addressing significant disorders of the central nervous system. The research findings and the perspectives they offer from the therapeutic standpoint are the focus of the here presented discussion.

The proposal of receptor-receptor interactions (RRIs) in the early 1980s broadened the view on the role of G protein-coupled receptors (GPCR) in the dynamics of the intercellular communication. RRIs, indeed, allow GPCR to operate not only as monomers but also as receptor complexes, in which the integration of the incoming signals depends on the number, spatial arrangement, and order of activation of the protomers forming the complex. The main biochemical mechanisms controlling the functional interplay of GPCR in the receptor complexes are direct allosteric interactions between protomer domains. The formation of these macromolecular assemblies has several physiologic implications in terms of the modulation of the signaling pathways and interaction with other membrane proteins. It also impacts on the emerging field of connectomics, as it contributes to set and tune the synaptic strength. Furthermore, recent evidence suggests that the transfer of GPCR and GPCR complexes between cells via the exosome pathway could enable the target cells to recognize/decode transmitters and/or modulators for which they did not express the pertinent receptors. Thus, this process may also open the possibility of a new type of redeployment of neural circuits. The fundamental aspects of GPCR complex formation and function are the focus of the present review article.

The integrative actions of the brain depend on the exchange of information among its computational elements. Hence, this phenomenon plays the key role in driving the complex dynamics of the central nervous system, in which true computations interact with noncomputational dynamical processes to generate brain representations of the body and of the body in the external world, and hence the finalistic behavior of the organism. In this context, it should be pointed out that, besides the intercellular interactions mediated by classical electrochemical signals, other types of interactions, namely, “cues” and “coercions,” also appear to be exploited by the system to achieve its function. The present review focuses mainly on cues present in the environment and on those produced by cells of the body, which “pervade” the brain and contribute to its dynamics. These cues can also be metabolic substrates, and, in most cases, they are of fundamental importance to brain function and the survival of the entire organism. Three of these highly pervasive cues will be analyzed in greater detail, namely, oxygen, carbon dioxide, and electromagnetic fields (EMF). Special emphasis will be placed on EMF, since several authors have suggested that these highly pervasive energy fluctuations may play an important role in the global integrative actions of the brain; hence, EMF signaling may transcend classical connectionist models of brain function. Thus the new concept of “broadcasted neuroconnectomics” has been introduced, which transcends the current connectomics view of the brain.

In this review, the aspects and further developments of the concept of homeostasis are discussed also in the perspective of their possible impact in the clinical practice, particularly as far as psychic homeostasis is concerned. A brief historical survey and comments on the concept of homeostasis and allostasis are presented to introduce our proposal that is based on the classical assumption of the interstitial fluid (ISF) as the internal medium for multicellular organisms. However, the new concept of a hierarchic role of ISF of the various organs is introduced. Additionally, it is suggested that particularly for some chemico-physical parameters, oscillatory rhythms within their proper set-ranges should be considered a fundamental component of homeostasis. Against this background, we propose that the brain ISF has the highest hierarchic role in human beings, providing the optimal environment, not simply for brain cell survival, but also for brain complex functions and the oscillatory rhythms of some parameters, such as cerebrospinal fluid sodium and brain ISF pressure waves, which may play a crucial role in brain physio-pathological states. Thus, according to this proposal, the brain ISF represents the real internal medium since the maintenance of its dynamic intra-set-range homeostasis is the main factor for a free and independent life of higher vertebrates. Furthermore, the evolutionary links between brain and kidney and their synergistic role in H2O/Na balance and brain temperature control are discussed. Finally, it is surmised that these two interrelated parameters have deep effects on the Central Nervous System (CNS) higher integrative actions such those linked to psychic homeostasis.

Humans are increasingly aware that their fate will depend on the wisdom they apply in interacting with the ecosystem. Its health is defined as the condition in which the ecosystem can deliver and continuously renew its fundamental services. A healthy ecosystem allows optimal interactions between humans and the other biotic/abiotic components, and only in a healthy ecosystem can humans survive and efficiently reproduce. Thus, both the human and ecosystem health should be considered together in view of their interdependence. The present article suggests that this relationship could be considered starting from the Hippocrates (460 BC&ndash, 370 BC) work &ldquo, On Airs, Waters, and Places&rdquo, to derive useful medical and philosophical implications for medicine which is indeed a topic that involves scientific as well as philosophical concepts that implicate a background broader than the human body. The brain-body-ecosystem medicine is proposed as a new more complete approach to safeguarding human health. Epidemiological data demonstrate that exploitation of the environment resulting in ecosystem damage affects human health and in several instances these diseases can be detected by modifications in the heart-brain interactions that can be diagnosed through the analysis of changes in heart rate variability.

The quite recent (at least on the evolutionary time scale) emergence of nervous systems in complex organisms enabled the living beings to build a wide-ranging model of the external world in order to predict and evaluate the outcomes of their actions. Such a process likely represents a real coding activity, since, by proper handling of information, it generates a mapping between the external environment and internal cerebral activity patterns. The patterns of neural activity that correspond to the final maps, however, emerge from the holistic assembly of a multilevel functional organization. Nerve tissue components, indeed, appear organized in compartments, also called functional modules (FM), that contain system components and circuits of different miniaturizations not only arranged to work together either in parallel or in series but also nested within each other. At least three levels can be recognized in a functional module and it is possible to point out that such a hierarchical organization of the brain circuits could be mirrored by a corresponding hierarchical organization of biocodes. This feature can also suggest the hypothesis that the same logic could operate also at system level to integrate FM into functional brain areas and to associate areas to generate the final map used by humans to image the external world and to imagine untestable worlds.

Our previous findings indicate that A2A and D2 receptors are co-expressed on adult rat striatal astrocytes and on the astrocyte processes, and that A2A-D2 receptor−receptor interaction can control the release of glutamate from the processes. Functional evidence suggests that the receptor−receptor interaction was based on heteromerization of native A2A and D2 receptors at the plasma membrane of striatal astrocyte processes. We here provide biochemical and biophysical evidence confirming that receptor−receptor interaction between A2A and D2 receptors at the astrocyte plasma membrane is based on A2A-D2 heteromerization. To our knowledge, this is the first direct demonstration of the ability of native A2A and D2 receptors to heteromerize on glial cells. As striatal astrocytes are recognized to be involved in Parkinson’s pathophysiology, the findings that adenosine A2A and dopamine D2 receptors can form A2A-D2 heteromers on the astrocytes in the striatum (and that these heteromers can play roles in the control of the striatal glutamatergic transmission) may shed light on the molecular mechanisms involved in the pathogenesis of the disease.

The discovery of receptor-receptor interactions (RRI) has expanded our understanding of the role that G protein-coupled receptors (GPCRs) play in intercellular communication. The finding that GPCRs can operate as receptor complexes, and not only as monomers, suggests that several different incoming signals could already be integrated at the plasma membrane level via direct allosteric interactions between the protomers that form the complex. Most research in this field has focused on neuronal populations and has led to the identification of a large number of RRI. However, RRI have been seen to occur not only in neurons but also in astrocytes and, outside the central nervous system, in cells of the cardiovascular and endocrine systems and in cancer cells. Furthermore, RRI involving the formation of macromolecular complexes are not limited to GPCRs, being also observed in other families of receptors. Thus, RRI appear as a widespread phenomenon and oligomerization as a common mechanism for receptor function and regulation. The discovery of these macromolecular assemblies may well have a major impact on pharmacology. Indeed, the formation of receptor complexes significantly broadens the spectrum of mechanisms available to receptors for recognition and signaling, which may be implemented through modulation of the binding sites of the adjacent protomers and of their signal transduction features. In this context, the possible appearance of novel allosteric sites in the receptor complex structure may be of particular relevance. Thus, the existence of RRI offers the possibility of new therapeutic approaches, and novel pharmacological strategies for disease treatment have already been proposed. Several challenges, however, remain. These include the accurate characterization of the role that the receptor complexes identified so far play in pathological conditions and the development of ligands specific to given receptor complexes, in order to efficiently exploit the pharmacological properties of these complexes.

The interaction between adenosine A2A and dopamine D2 receptors in striatal neurons is a well-established phenomenon and has opened up new perspectives on the molecular mechanisms involved in Parkinson's disease. However, it has barely been investigated in astrocytes. Here, we show by immunofluorescence that both A2A and D2 receptors are expressed in adult rat striatal astrocytes in situ, and investigate on presence, function, and interactions of the receptors in the astrocyte processes-acutely prepared from the adult rat striatum-and on the effects of homocysteine on the A2A-D2 receptor-receptor interaction. We found that A2A and D2 receptors were co-expressed on vesicular glutamate transporter-1-positive astrocyte processes, and confirmed that A2A-D2 receptor-receptor interaction controlled glutamate release-assessed by measuring the [3H]D-aspartate release-from the processes. The complexity of A2A-D2 receptor-receptor interaction is suggested by the effect of intracellular homocysteine, which reduced D2-mediated inhibition of glutamate release (homocysteine allosteric action on D2), without interfering with the A2A-mediated antagonism of the D2 effect (maintained A2A-D2 interaction). Our findings indicate the crucial integrative role of A2A-D2 molecular circuits at the plasma membrane of striatal astrocyte processes. The fact that homocysteine reduced D2-mediated inhibition of glutamate release could provide new insights into striatal astrocyte-neuron intercellular communications. As striatal astrocytes are recognized to be involved in Parkinson's pathophysiology, these findings may shed light on the pathogenic mechanisms of the disease and contribute to the development of new drugs for its treatment.

Each living organism is a component of an ecosystem, as Bateson stated, “ The unit of survival is organism plus environment ”. Accordingly, the main aim of the present article is to analyse the place of human beings in the ecosystem, taking into account their peculiar characteristic of contraption-makers, and hence of modifiers of the ecosystem. This characteristic has been of paramount importance to the evolutionary success of homo sapiens, but, especially in the last century, it has been potentially dangerous for the entire ecosystem, and hence for human survival. The term “Hubris” refers to the mis-exaptation of these creative human capabilities, which can result in “mental illness” and prompt homo sapiens to believe in his godlike power over the ecosystem. Some neurobiological aspects related to Hubris are briefly discussed in relation to the pathogenetic changes caused by human overexploitation of the ecosystem. In conclusion, there is an urgent need for humans to take long-term responsibility for their dealings with the ecosystem, not only because severe physical and mental illnesses are caused by dangerous man-made alterations of the ecosystem, but also because these psychic disorders are part of a positive feedback that is able to shatter crucial components of the entire “survival unit”. A brief illustration of this point from the standpoint of available mathematical models of human-environment interactions can be found in the ‘Appendix A’.

Investigations of brain complex integrative actions should consider beside neural networks, glial, extracellular molecular, and fluid channels networks. The present paper proposes that all these networks are assembled into the brain hyper-network that has as fundamental components, the tetra-partite synapses, formed by neural, glial, and extracellular molecular networks. Furthermore, peri-synaptic astrocytic processes by modulating the perviousness of extracellular fluid channels control the signals impinging on the tetra-partite synapses. It has also been surmised that global signalling via astrocytes networks and highly pervasive signals, such as electromagnetic fields (EMFs), allow the appropriate integration of the various networks especially at crucial nodes level, the tetra-partite synapses. As a matter of fact, it has been shown that astrocytes can form gap-junction-coupled syncytia allowing intercellular communication characterised by a rapid and possibly long-distance transfer of signals. As far as the EMFs are concerned, the concept of broadcasted neuroconnectomics (BNC) has been introduced to describe highly pervasive signals involved in resetting the information handling of brain networks at various miniaturisation levels. In other words, BNC creates, thanks to the EMFs, generated especially by neurons, different assemblages among the various networks forming the brain hyper-network. Thus, it is surmised that neuronal networks are the "core components" of the brain hyper-network that has as special "nodes" the multi-facet tetra-partite synapses. Furthermore, it is suggested that investigations on the functional plasticity of multi-partite synapses in response to BNC can be the background for a new understanding and perhaps a new modelling of brain morpho-functional organisation and integrative actions.

Multiple players are involved in the brain integrative action besides the classical neuronal and astrocyte networks. In the past, the concept of complex cellular networks has been introduced to indicate that all the cell types in the brain can play roles in its integrative action. Intercellular communication in the complex cellular networks depends not only on well-delimited communication channels (wiring transmission) but also on diffusion of signals in physically poorly delimited extracellular space pathways (volume transmission). Thus, the extracellular space and the extracellular matrix are the main players in the intercellular communication modes in the brain. Hence, the extracellular matrix is an ‘intelligent glue’ that fills the brain and, together with the extracellular space, contributes to the building-up of the complex cellular networks. In addition, the extracellular matrix is part of what has been defined as the global molecular network enmeshing the entire central nervous system, and plays important roles in synaptic contact homeostasis and plasticity. From these premises, a concept is introduced that the global molecular network, by enmeshing the central nervous system, contributes to the brain holistic behavior. Furthermore, it is suggested that plastic ‘brain compartments’ can be detected in the central nervous system based on the astrocyte three-dimensional tiling of the brain volume and on the existence of local differences in cell types and extracellular space fluid and extracellular matrix composition. The relevance of the present view for neuropsychiatry is discussed. A glossary box with terms and definitions is provided.

Already in the 1960s the architecture and pharmacology of the brainstem dopamine (DA) and noradrenaline (NA) neurons with formation of vast numbers of DA and NA terminal plexa of the central nervous system (CNS) indicated that they may not only communicate via synaptic transmission. In the 1980s the theory of volume transmission (VT) was introduced as a major communication together with synaptic transmission in the CNS. VT is an extracellular and cerebrospinal fluid transmission of chemical signals like transmitters, modulators etc. moving along energy gradients making diffusion and flow of VT signals possible. VT interacts with synaptic transmission mainly through direct receptor-receptor interactions in synaptic and extrasynaptic heteroreceptor complexes and their signaling cascades. The DA and NA neurons are specialized for extrasynaptic VT at the soma-dendrtitic and terminal level. The catecholamines released target multiple DA and adrenergic subtypes on nerve cells, astroglia and microglia which are the major cell components of the trophic units building up the neural-glial networks of the CNS. DA and NA VT can modulate not only the strength of synaptic transmission but also the VT signaling of the astroglia and microglia of high relevance for neuron-glia interactions. The catecholamine VT targeting astroglia can modulate the fundamental functions of astroglia observed in neuroenergetics, in the Glymphatic system, in the central renin-angiotensin system and in the production of long-distance calcium waves. Also the astrocytic and microglial DA and adrenergic receptor subtypes mediating DA and NA VT can be significant drug targets in neurological and psychiatric disease.

Evidence for striatal A2A-D2 heterodimers has led to a new perspective on molecular mechanisms involved in schizophrenia and Parkinson's disease. Despite the increasing recognition of astrocytes’ participation in neuropsychiatric disease vulnerability, involvement of striatal astrocytes in A2A and D2 receptor signal transmission has never been explored. Here, we investigated the presence of D2 and A2A receptors in isolated astrocyte processes prepared from adult rat striatum by confocal imaging; the effects of receptor activation were measured on the 4-aminopyridine-evoked release of glutamate from the processes. Confocal analysis showed that A2A and D2 receptors were co-expressed on the same astrocyte processes. Evidence for A2A-D2 receptor-receptor interactions was obtained by measuring the release of the gliotransmitter glutamate: D2 receptors inhibited the glutamate release, while activation of A2A receptors, per se ineffective, abolished the effect of D2 receptor activation. The synthetic D2 peptide VLRRRRKRVN corresponding to the receptor region involved in electrostatic interaction underlying A2A-D2 heteromerization abolished the ability of the A2A receptor to antagonize the D2 receptor-mediated effect. Together, the findings are consistent with heteromerization of native striatal astrocytic A2A-D2 receptors that via allosteric receptor-receptor interactions could play a role in the control of striatal glutamatergic transmission. These new findings suggest possible new pathogenic mechanisms and/or therapeutic approaches to neuropsychiatric disorders. This article is protected by copyright. All rights reserved.

Cellular network architecture plays a crucial role as the structural substrate for the brain functions. Therefore, it represents the main rationale for the emerging field of connectomics, defined as the comprehensive study of all aspects of central nervous system connectivity. Accordingly, in the present paper the main emphasis will be on the communication processes in the brain, namely wiring transmission (WT), i.e. the mapping of the communication channels made by cell components such as axons and synapses, and volume transmission (VT), i.e. the chemical signal diffusion along the interstitial brain fluid pathways. Considering both processes can further expand the connectomics concept, since both WT-connectomics and VT-connectomics contribute to the structure of the brain connectome. A consensus exists that such a structure follows a hierarchical or nested architecture, and macro-, meso- and microscales have been defined. In this respect, however, several lines of evidence indicate that a nanoscale (nano-connectomics) should also be considered to capture direct protein-protein allosteric interactions such as those occurring, for example, in receptor-receptor interactions at the plasma membrane level. In addition, emerging evidence points to novel mechanisms likely playing a significant role in the modulation of intercellular connectivity, increasing the plasticity of the system and adding complexity to its structure. In particular, the roamer type of VT (i.e. the intercellular transfer of RNA, proteins and receptors by extracellular vesicles) will be discussed since it allowed us to introduce a new concept of ‘transient changes of cell phenotype’, that is the transient acquisition of new signal release capabilities and/or new recognition/decoding apparatuses.

Some neurobiological aspects and social consequences of religious beliefs are briefly discussed. A basic aspect to be considered is the capability of several living beings to prospect future scenarios. In this context, however, it has to be underlined that only humans know that they have to die. Consequently, all human cultures have proposed dreams, visions and religious beliefs to dispel the fear of death. Awareness of the end of life has played a fundamental role in the emergence of religious beliefs. The social aspects of religions will be considered from Bloch’s perspective that modern humans are the only living beings capable of peculiar social inter-relationships, namely the transcendental social, which consists of the creation of essentialized roles and groups that exist separately from the individual who holds them. In other words, the transcendental social bonds not only real groups, such as tribes, clans or nations, but also imaginary groups, such as ancestors or gods, thereby allowing the emergence of religion as a uniquely human activity. In the present paper, it is suggested that the concept of exaptation can shed some light on the origin of religions and on their potential positive effects on individual lives and human societies. On the other hand, the concept of mis-exaptation can shed some light on the possible perverse side-effects of religious beliefs. Thus, some aspects of the possible conceptual and neurobiological links between exaptation and mis-exaptation of the religious beliefs will be analyzed.

Several types of D2R and D1R heteroreceptor complexes were discovered in the indirect and direct pathways of the striatum, respectively. The hypothesis is given that changes in the function of the dopamine heteroreceptor complexes may help us understand the molecular mechanisms underlying the motor complications of long-term therapy in Parkinson's disease (PD) with l-DOPA and dopamine receptor agonists.In the indirect pathway, the potential role of the A2AR-D2R, A2AR-D2R-mGluR5 and D2R-NMDAR heteroreceptor complexes in PD are covered and in the direct pathway, the D1R-D3R, A1R-D1R, D1R-NMDAR and putative A1R-D1R-D3R heteroreceptor complexes.One explanation for the more powerful ability of l-DOPA treatment versus treatment with the partial dopamine receptor agonist/antagonist activity to induce dyskinesias, may be that dopamine formed from l-DOPA acts as a full agonist. The field of D1R and D2R heteroreceptor complexes in the CNS opens up a new understanding of the wearing off of the antiparkinson actions of l-DOPA and dopamine receptor agonists and the production of l-DOPA-induced dyskinesias. It can involve a reorganization of the D1R and D2R heteroreceptor complexes and a disbalance of the D1R and D2R homomers versus non-dopamine receptor homomers in the direct and indirect pathways.

The tridecapeptide neurotensin (NT) acts as neurotransmitter in the central nervous system and in the periphery. NT and NT receptors are largely localized in dopamine (DA)-enriched regions of the mammalian brain. Accordingly, numerous studies indicate the presence of close functional interactions between DA neurons and the peptide. Among others mechanisms, it has been suggested that NT could modulate nigrostriatal, mesolimbic and meso-cortical DA transmission through an antagonistic receptor-receptor interaction between the NT receptor subtype 1 (NTS1) and the dopamine D2 receptor (D2R). In particular, it was originally demonstrated that the peptide reduces the D2R agonist affinity in striatal sections and in striatal membrane preparations. These effects could be a consequence of the direct allosteric NTS1/D2 receptor interactions leading to a decrease in the DA agonist affinity at the D2 receptor. Several neurochemical, biochemical and co-immunoprecipitation data have successively reinforced the indication of the presence of direct NTS1-D2 receptor interactions in the mammalian brain. The present mini-review attempts to provide a summary of current knowledge, mainly emerging from our microdialysis studies, supporting the presence of a NTS1/D2 receptor heteromer in the brain. The pre and post-synaptic mechanisms underlying the involvement of this heteromer in the striatopallidal GABA and mesocorticolimbic DA neurotransmission are discussed especially for their relevance in Parkinson's disease and schizophrenia, respectively.

Striatal dopamine adenosine A2A and D2 receptors interact to modulate some aspects of motor and motivational function. The demonstration of A2A/D2 receptor heteromerization in living cells constituted a progress for understanding the neurobiology of dopamine D2 and adenosine A2A receptors. In fact, the existence of putative striatalA2A/D2 receptor heteromers has been suggested to be important for striatal function under both normal and pathological conditions, such as Parkinson's disease. Consequently, the antagonistic A2A-D2 receptor interactions in a putative striatal receptor heteromer on striato-pallidal GABA neuron led to the introduction of A2A receptor antagonists as possible anti- Parkinsonian drugs. The present mini-review briefly summarizes the main findings supporting the presence of antagonistic A2A-D2 receptor interactions in putative receptor heteromers in the basal ganglia. Special emphasis is given to in vivo microdialysis findings demonstrating the functional role putative A2A/D2 heteromers on striato-pallidal GABA neurons play in the modulation of this pathway, in which A2A receptors inhibit D2 receptor signaling. The possible relevance of compounds targeting the putative striatal A2A/D2 heteromer in the Parkinson's disease pharmacological treatment is also discussed.

The effects of cocaine (150 nM, 300 nM, and 150 μM) on human glioblastoma cell cultures were studied on tunneling nanotube formation (1-h cocaine treatment) and extracellular vesicle release (1-, 3-, and 8-h cocaine treatment). Cocaine significantly increased the number of tunneling nanotubes only at the lowest concentration used. The release of extracellular vesicles (mainly exosomes) into the medium was stimulated by cocaine at each concentration used with a maximum effect at the highest concentration tested (150 μM). Moreover, cocaine (150 nM) significantly increased the number of vesicles with 61-80 nm diameter while at concentrations of 300 nM and 150 μM, and the smaller vesicles (30-40 nm diameter) were significantly increased with a reduction of the larger vesicles (41-60 nm diameter). A time dependence in the release of extracellular vesicles was observed. In view of the proposed role of these novel intercellular communication modes in the glial-neuronal plasticity, it seems possible that they can participate in the processes leading to cocaine addiction. The molecular target/s involved in these cocaine effects could be specific molecular components of plasma membrane lipid rafts and/or cocaine-induced modifications in cytoplasmic lipid composition.

Dopamine D2LR-serotonin 5-HT2AR heteromers were demonstrated in HEK293 cells after cotransfection of the two receptors and shown to have bidirectional receptor–receptor interactions. In the current study the existence of D2L-5-HT2A heteroreceptor complexes was demonstrated also in discrete regions of the ventral and dorsal striatum with in situ proximity ligation assays (PLA). The hallucinogenic 5-HT2AR agonists LSD and DOI but not the standard 5-HT2AR agonist TCB2 and 5-HT significantly increased the density of D2like antagonist 3H-raclopride binding sites and significantly reduced the pKiH values of the high affinity D2R agonist binding sites in 3H-raclopride/DA competition experiments. Similar results were obtained in HEK293 cells and in ventral striatum. The effects of the hallucinogenic 5-HT2AR agonists on D2R density and affinity were blocked by the 5-HT2A antagonist ketanserin. In a forskolin-induced CRE-luciferase reporter gene assay using cotransfected but not D2R singly transfected HEK293 cells DOI and LSD but not TCB2 significantly enhanced the D2LR agonist quinpirole induced inhibition of CRE-luciferase activity. Haloperidol blocked the effects of both quinpirole alone and the enhancing actions of DOI and LSD while ketanserin only blocked the enhancing actions of DOI and LSD. The mechanism for the allosteric enhancement of the D2R protomer recognition and signalling observed is likely mediated by a biased agonist action of the hallucinogenic 5-HT2AR agonists at the orthosteric site of the 5-HT2AR protomer. This mechanism may contribute to the psychotic actions of LSD and DOI and the D2-5-HT2A heteroreceptor complex may thus be a target for the psychotic actions of hallunicogenic 5-HT2A agonists.

New findings show that neurotrophic and antidepressant effects of 5-HT in brain can, in part, be mediated by activation of the 5-HT1A receptor protomer in the hippocampal and raphe FGFR1-5-HT1A heteroreceptor complexes enhancing the FGFR1 signaling. The dynamic agonist modulation of the FGFR1-5-HT1A heteroreceptor complexes and their recruitment of β-arrestin is now determined in cellular models with focus on its impact on 5-HT1AR and FGFR1 homodimerization in the heteroreceptor complexes based on BRET(2) assays. The findings show that coagonist treatment with 8-OH-DPAT and FGF2 but not treatment with the 5-HT1A agonist alone markedly increases the BRETmax values and significantly reduces the BRET50 values of 5HT1A homodimerization. The effects of FGF2 or FGF20 with or without the 5-HT1A agonist were also studied on the FGFR1 homodimerization of the heteroreceptor complexes. FGF2 produced a marked and rapid increase in FGFR1 homodimerization which partially declined over a 10min period. Cotreatment with FGF2 and 5-HT1A agonist blocked this decline in FGFR1 homodimerization. Furthermore, FGF2 alone produced a small increase in the BRET(2) signal from the 5-HT1A-β-arrestin2 receptor-protein complex which was additive to the marked effect of 8-OH-DPAT alone. Taken together, the participation of 5-HT1A and FGFR1 homodimers and recruitment of β-arrestin2 was demonstrated in the FGFR1-5-HT1A heteroreceptor complexes upon agonist treatments.

Volume transmission (VT) is a widespread mode of intercellular communication that occurs in the extracellular fluid (ECF) and in the cerebrospinal fluid (CSF) of the brain with VT signals moving from source to target cells via energy gradients leading to diffusion and convection (flow). The VT channels are diffuse forming a plexus in the extracellular space, while in wiring transmission (WT) the channels (axons, terminals) are private. The speed is slow (seconds-minutes) in VT while rapid in the millisecond range in WT. The extracellular space is the substrate for VT, which is modulated by the extracellular matrix. Extrasynaptic VT is linked to synaptic transmission and likely often takes place due to incomplete diffusion barriers with the synaptic transmitter reaching extrasynaptic domains of the pre-and post-synaptic membrane of the synapse, the astroglia, and even adjacent synapses. Indications exist for the existence of striatal D2-like receptor-mediated extrasynaptic form of dopamine (DA) VT at the local circuit level in vivo in the human striatum. Synaptic glutamate via extrasynaptic VT can act on extrasynaptic metabotropic glutamate receptors located on the astroglia leading to Ca(2+) mediated astrocytic glutamate release into the extracellular space (ECS). Long distance peptide VT and CSF VT is the major long distance VT with distances more than 1 mm and flow in the CSF. Indications for long distance VT of beta-endorphin and oxytocin are obtained. We propose that monogamy in the female prairie vole may take place through an increase in oxytocin VT, especially in nucleus accumbens. Release of extracellular vesicles containing receptors, proteins, RNAs and mtDNA from cellular networks in the central nervous system (CNS) into the ECF and CSF may be a fundamental communication in the CNS. It represents a special form of volume transmission, the Roamer subtype of VT. It may greatly contribute to dynamic events of synaptic plasticity but also to spread of pathological proteins in protein conformational disorders. VT also occurs in the peripheral nervous system and associated cells. Short and long distance VT may take place in meridian channels via diffusion and flow in the interstitial fluid. Acupuncture can produce VT signals by releasing transmitters and modulators from nerve terminals and mast cells.

Our hypothesis is that allosteric receptor-receptor interactions in homo- and heteroreceptor complexes may form the molecular basis of learning and memory. This principle is illustrated by showing how cocaine abuse can alter the adenosine A2AR-dopamine D2R heterocomplexes and their receptor-receptor interactions and hereby induce neural plasticity in the basal ganglia. Studies with A2AR ligands using cocaine self-administration procedures indicate that antagonistic allosteric A2AR-D2R heterocomplexes of the ventral striatopallidal GABA antireward pathway play a significant role in reducing cocaine induced reward, motivation, and cocaine seeking. Anticocaine actions of A2AR agonists can also be produced at A2AR homocomplexes in these antireward neurons, actions in which are independent of D2R signaling. At the A2AR-D2R heterocomplex, they are dependent on the strength of the antagonistic allosteric A2AR-D2R interaction and the number of A2AR-D2R and A2AR-D2R-sigma1R heterocomplexes present in the ventral striatopallidal GABA neurons. It involves a differential cocaine-induced increase in sigma1Rs in the ventral versus the dorsal striatum. In contrast, the allosteric brake on the D2R protomer signaling in the A2AR-D2R heterocomplex of the dorsal striatopallidal GABA neurons is lost upon cocaine self-administration. This is potentially due to differences in composition and allosteric plasticity of these complexes versus those in the ventral striatopallidal neurons.

Cell death represents the final outcome of several pathological conditions of the central nervous system and available evidence suggests that in both acute injuries and neurodegenerative diseases it is often associated with mitochondrial dysfunction. Thus, the possibility to prevent mitochondrial events involved in cell death might represent efficient tools to limit neuronal damage. In recent years, increased attention has been paid to the endogenous protein neuroglobin, since accumulating evidence showed that its high expression was associated with preserved mitochondrial function and to an increased survival of nerve cells in vitro and in vivo in a variety of experimental models of cell insult. The biological and structural features of neuroglobin and the mitochondria-related mechanisms of neuroglobin-induced neuroprotection will be here briefly discussed. In this respect, the inhibition of the intrinsic pathway of apoptosis emerges as a key neuroprotective effect induced by the protein. These findings could open the possibility to develop efficient neuroglobin-mediated therapeutic strategies aimed at minimizing the neuronal cell death occurring in impacting neurological pathologies like stroke and neurodegenerative diseases.

From the morphological point of view, the nervous system exhibits a fractal, self-similar geometry at various levels of observations, from single cells up to cell networks. From the functional point of view, it is characterized by a hierarchic organization in which self-similar structures (networks) of different miniaturizations are nested within each other. In particular, neuronal networks, interconnected to form neuronal systems, are formed by neurons, which operate thanks to their molecular networks, mainly having proteins as components that via protein–protein interactions can be assembled in multimeric complexes working as micro-devices. On this basis, the term “self-similarity logic” was introduced to describe a nested organization where at the various levels almost the same rules (logic) to perform operations are used. Self-similarity and self-similarity logic appear intimately linked to the biophysical evidence for the nervous system being a pattern-forming system that can switch flexibly from one coherent state to another. Thus, they can represent key concepts to describe its complexity and its concerted, holistic behavior.

Several ion channels can be randomly and spontaneously in an open state, allowing the exchange of ion fluxes between extracellular and intracellular environments. We propose that the random changes in the state of ion channels could be also due to proteins exploring their energy landscapes. Indeed, proteins can modify their steric conformation under the effects of the physicochemical parameters of the environments with which they are in contact, namely, the extracellular, intramembrane and intracellular environments. In particular, it is proposed that the random walk of proteins in their energy landscape is towards attractors that can favor the open or close condition of the ion channels and/or intrinsic activity of G-protein-coupled receptors. The main aspect of the present proposal is that some relevant physicochemical parameters of the environments (e.g. molecular composition, temperature, electrical fields) with which some signaling-involved plasma membrane proteins are in contact alter their conformations. In turn, these changes can modify their information handling via a modulatory action on their random walk towards suitable attractors of their energy landscape. Thus, spontaneous and/or signal-triggered electrical activities of neurons occur that can have emergent properties capable of influencing the integrative actions of brain networks. Against this background, Cook’s hypothesis on ‘cell sentience’ is developed by proposing that physicochemical parameters of the environments with which the plasma-membrane proteins of complex cellular networks are in contact fulfill a fundamental role in their spontaneous and/or signal-triggered activity. Furthermore, it is proposed that a specialized organelle, the primary cilium, which is present in most cells (also neurons and astrocytes), could be of peculiar importance to pick up chemical signals such as ions and transmitters and to detect physical signals such as pressure waves, thermal gradients, and local field potentials.

Conformational protein diseases of the human central nervous system represent a subject that has crucial theoretical and medical implications. They include several important neurodegenerative diseases, such as Alzheimer's, Parkinson's, Huntington's and Creutzfeldt-Jacob's diseases, amyotrophic lateral sclerosis, and the tauopathies. They occur when soluble proteins undergo conformational rearrangements becoming capable of aggregate into β-sheets conformations leading to the production of insoluble complexes known as amyloid deposits, that accumulate and lead to neurons and glial cells death. Theoretical and experimental evidence indicates that a key role in the conformational changes leading to amyloid formation is played by short sequence stretches within a given protein. Thus, the identification of protein regions potentially involved in aggregate formation and the characterization of their properties are relevant questions in the study of conformational proteins diseases. To address these questions, bioinformatics methods might provide an important contribution, suggesting possible mechanisms of protein aggregation, and focusing and orienting the experimental work. Thus, in the first part of the present review bioinformatics methods specifically attempting to predict aggregation-prone regions in proteins will be briefly described. Furthermore, the results provided by the combined use of some of them to analyze a set of particularly important proteins involved in human degenerative diseases will be discussed.

The control of glutamatergic corticostriatal transmission is essential for the induction and expression of plasticity mechanisms in the striatum, a phenomenon thickly regulated by G protein-coupled receptors (GPCRs). Interestingly, in addition to dopamine receptors, adenosine and metabotropic glutamate receptors also play a key role in striatal functioning. The existence of a supramolecular organization (i.e. oligomer) containing dopamine, adenosine and metabotropic glutamate receptors in the striatal neurons is now being widely accepted by the scientific community. Indeed, these oligomers may enhance the diversity and performance by which extracellular striatal signals are transferred to the G-proteins in the process of receptor transduction, and also may allow unpredictable receptor-receptor allosteric regulations. Overall, here we want to review how formations of adenosine, dopamine and metabotropic glutamate receptors-containing oligomers impinge into striatal functioning in both normal and pathological conditions. This article is part of a Special Issue entitled: Brain Integration.

This article is focused on understanding the mechanisms for the interactions between the central catecholamine (CA) and oxytocin (OXY) neurons and their relevance for brain function especially social behaviour in the field of pair bonding. Such a topic is analysed under two perspectives namely the intercellular communication modes between CA and OXT neurons and the molecular integrative mechanisms at the plasma membrane level between their respective decoding systems. As a matter of fact, recent observations strongly indicate a major role of volume transmission and receptor-receptor interactions in the CA/OXT neuron interplay in the brain control of social behaviour and pair bonding. This article is part of a Special Issue entitled: Brain Integration.

Unique mental abilities have been crucial for evolutionary success of Homo sapiens and for the development of his complex social organization. However, these abilities have also become a target for mental disorders which often result in a reduced fitness and in conflicts between the individual and the conventions of society. To account for this evolutionary maladaptation, we advance a new concept: that of "mis-exaptation", derived from SJ Gould and E Vrba's concept of exaptation. Mis-exaptation is a characteristic which, although it may confer positive effects in one field of activity, may reach an inappropriate degree of specialisation to have deleterious effects in that or in another field thereby leading to a decrease in fitness of the individual. This paper considers "inner speech" as an exaptation. Although inner speech is usually a positive aid to learning and reasoning, it may also favour the emergence of mental disturbances, such as the auditory hallucinations which are characteristic of schizophrenia. There is, nevertheless, a possible evolutionary value in mis-exaptational inner speech; two traits associated with the mis-exapted state would be altruistic behaviour and heightened creativity, the latter being over-expressed in relatives of schizophrenic patients. A possible solution for the evolutionary-genetic paradox posed by altruism and schizophrenia arising from mis-exaptation will be suggested in the light of a cryptic genetic repertoire. A selection of illustrative examples of each of these mental states is presented as they appear in the pages of the European literature. This article is part of a Special Issue entitled: Brain Integration.