Brain energetics and the connectionist concept in cognitive neuroscience.

One of the central paradigms of modern neuroscience is the connectionist concept suggesting that the brain's cognitive functions are carried out at the level of neural networks through complex interactions among neurons. This concept considers neurons as simple network elements whose function is limited to generating electrical potentials and transmitting signals to other neurons. Here, I focus on the neuroenergetic aspect of cognitive functions and argue that many findings from this field challenge the concept that cognitive functions are performed exclusively at the level of neural circuits. Two of these findings are particularly foretelling. First, activation of the cerebral cortex in humans (sensory stimulation or solving cognitive problems) is not associated with a significant increase in energy demand. Second, the energetic cost of the brain per unit mass in primates, including Homo sapiens, is approximately proportional to the number of cerebral neurons but not to the number of synapses, the complexity of neural networks, or the level of brain's intellectual abilities. These findings contradict the predictions of the connectionist concept. Rather, they suggest that cognitive functions are generated by intraneuronal mechanisms that do not require much energy. In this context, interactions among neurons would serve to coordinate activities of neurons performing elementary cognitive functions. This function of the network mechanisms also does not require much energy.

Memory: Synaptic or Cellular, That Is the Question.

According to the commonly accepted opinion, memory engrams are formed and stored at the level of neural networks due to a change in the strength of synaptic connections between neurons. This hypothesis of synaptic plasticity (HSP), formulated by Donald Hebb in the 1940s, continues to dominate the directions of experimental studies and the interpretations of experimental results in the field. The universal acceptance of the HSP has transformed it from a hypothesis into an incontrovertible theory. In this article, I show that the entire body of experimental and clinical data obtained in studies of long-term memory in mammals and humans is inconsistent with the HSP. Instead, these data suggest that long-term memory is formed and stored at the intracellular level where it is reliably protected from ongoing synaptic activity, including pathological epileptic activity. It seems that the generally accepted HSP became a serious obstacle to understanding the mechanisms of memory and that progress in this field requires rethinking this doctrine and shifting experimental efforts toward exploring the intracellular mechanisms.

Alzheimer's Disease: From Amyloid to Autoimmune Hypothesis.

Although Alzheimer's disease (AD) was described over a century ago, there are no effective approaches to its prevention and treatment. Such a slow progress is explained, at least in part, by our incomplete understanding of the mechanisms underlying the pathogenesis of AD. Here, I champion a hypothesis whereby AD is initiated on a disruption of the blood-brain barrier (BBB) caused by either genetic or non-genetic risk factors. The BBB disruption leads to an autoimmune response against pyramidal neurons located in the allo- and neocortical structures involved in memory formation and storage. The response caused by the adaptive immune system is not strong enough to directly kill neurons but may be sufficient to make them selectively vulnerable to neurofibrillary pathology. This hypothesis is based on the recent data showing that memory formation is associated with epigenetic chromatin modifications and, therefore, may be accompanied by expression of memory-specific proteins recognized by the immune system as "non-self" antigens. The autoimmune hypothesis is testable, and I discuss potential ways for its experimental and clinical verification. If confirmed, this hypothesis can radically change therapeutic approaches to AD prevention and treatment.

Neurons versus Networks: The Interplay between Individual Neurons and Neural Networks in Cognitive Functions.

The main paradigm of cognitive neuroscience is the connectionist concept postulating that the higher nervous activity is performed through interactions of neurons forming complex networks, whereas the function of individual neurons is restricted to generating electrical potentials and transmitting signals to other cells. In this article, I describe the observations from three fields-neurolinguistics, physiology of memory, and sensory perception-that can hardly be explained within the constraints of a purely connectionist concept. Rather, these examples suggest that cognitive functions are determined by specific properties of individual neurons and, therefore, are likely to be accomplished primarily at the intracellular level. This view is supported by the recent discovery that the brain's ability to create abstract concepts of particular individuals, animals, or places is performed by neurons ("concept cells") sparsely distributed in the medial temporal lobe.

Alzheimer disease and cellular mechanisms of memory storage.

Most ongoing efforts to combat Alzheimer disease (AD) are focused on treating its clinical symptoms, but the neuropathologic changes underlying AD appear decades earlier and become essentially irreversible by the time the disease reaches its clinical stages. This necessitates treating AD at preclinical stages, which requires a better understanding of the primary mechanisms leading to AD pathology. Here I argue that such an understanding calls for addressing perhaps the most puzzling question in AD-why the underlying pathology selectively impairs neurons that are involved in memory formation and storage. Memory formation is associated with epigenetic chromatin modifications and may, therefore, be accompanied by the synthesis of proteins unique to neurons involved in memory. These proteins could be recognized by the immune system as "nonself" antigens. This does not happen in the healthy brain because of its isolation from the immune system by the blood-brain barrier (BBB). All risk factors for AD impair the BBB, which may allow the immune system to attack memory-involved neurons and make them vulnerable to AD-associated pathology. This hypothesis is testable and, if confirmed, could redirect therapeutic efforts toward maintaining BBB integrity people belonging to AD risk groups rather than treating them when it is too late.

Why Alzheimer's disease starts with a memory impairment: neurophysiological insight.

Alzheimer's disease is a neurodegenerative disease whose sole initial symptom is memory impairment. However, the mechanisms which make the neurons involved in learning and memory particularly vulnerable to the formation of amyloid plaques and neurofibrillary tangles remain completely unknown. Here, I propose a hypothesis that may resolve this puzzle. A growing body of evidence suggests that memory formation involves epigenetic mechanisms that regulate patterns of gene expression. Therefore, it is conceivable that the process of memory consolidation may include the synthesis of novel proteins that are recognized by the immune system as "non-self" antigens. Normally, neurons involved in formation and storage of memory are isolated from the organism's immune system by the blood-brain barrier. Since all known genetic and environmental risk factors for Alzheimer's disease can compromise this barrier, I hypothesize that the disease is initiated as an autoimmune reaction against the memory-bearing neurons. This reaction gradually makes these neurons vulnerable to the subsequent formation of amyloid plaques and neurofibrillary tangles. This hypothesis suggests that early therapy of Alzheimer's disease could be devoted to preventing impairments in the blood-brain barrier. Recent evidence that formation of the blood-brain barrier is controlled via the Wnt/beta-catenin signaling pathway may suggest potential directions to addressing this problem.

Two functions of early language experience.

The unique human ability of linguistic communication, defined as the ability to produce a practically infinite number of meaningful messages using a finite number of lexical items, is determined by an array of "linguistic" genes, which are expressed in neurons forming domain-specific linguistic centers in the brain. In this review, I discuss the idea that infants' early language experience performs two complementary functions. In addition to allowing infants to assimilate the words and grammar rules of their mother language, early language experience initiates genetic programs underlying language production and comprehension. This hypothesis explains many puzzling characteristics of language acquisition, such as the existence of a critical period for acquiring the first language and the absence of a critical period for the acquisition of additional language(s), a similar timetable for language acquisition in children belonging to families of different social and cultural status, the strikingly similar timetables in the acquisition of oral and sign languages, and the surprisingly small correlation between individuals' final linguistic competence and the intensity of their training. Based on the studies of microcephalic individuals, I argue that genetic factors determine not only the number of neurons and organization of interneural connections within linguistic centers, but also the putative internal properties of neurons that are not limited to their electrophysiological and synaptic properties.

"The seven sins" of the Hebbian synapse: can the hypothesis of synaptic plasticity explain long-term memory consolidation?

Memorizing new facts and events means that entering information produces specific physical changes within the brain. According to the commonly accepted view, traces of memory are stored through the structural modifications of synaptic connections, which result in changes of synaptic efficiency and, therefore, in formations of new patterns of neural activity (the hypothesis of synaptic plasticity). Most of the current knowledge on learning and initial stages of memory consolidation ("synaptic consolidation") is based on this hypothesis. However, the hypothesis of synaptic plasticity faces a number of conceptual and experimental difficulties when it deals with potentially permanent consolidation of declarative memory ("system consolidation"). These difficulties are rooted in the major intrinsic self-contradiction of the hypothesis: stable declarative memory is unlikely to be based on such a non-stable foundation as synaptic plasticity. Memory that can last throughout an entire lifespan should be "etched in stone." The only "stone-like" molecules within living cells are DNA molecules. Therefore, I advocate an alternative, genomic hypothesis of memory, which suggests that acquired information is persistently stored within individual neurons through modifications of DNA, and that these modifications serve as the carriers of elementary memory traces.

"Scientific roots" of dualism in neuroscience.

Although the dualistic concept is unpopular among neuroscientists involved in experimental studies of the brain, neurophysiological literature is full of covert dualistic statements on the possibility of understanding neural mechanisms of human consciousness. Particularly, the covert dualistic attitude is exhibited in the unwillingness to discuss neural mechanisms of consciousness, leaving the problem of consciousness to psychologists and philosophers. This covert dualism seems to be rooted in the main paradigm of neuroscience that suggests that cognitive functions, such as language production and comprehension, face recognition, declarative memory, emotions, etc., are performed by neural networks consisting of simple elements. I argue that neural networks of any complexity consisting of neurons whose function is limited to the generation of electrical potentials and the transmission of signals to other neurons are hardly capable of producing human mental activity, including consciousness. Based on results obtained in physiological, morphological, clinical, and genetic studies of cognitive functions (mainly linguistic ones), I advocate the hypothesis that the performance of cognitive functions is based on complex cooperative activity of "complex" neurons that are carriers of "elementary cognition." The uniqueness of human cognitive functions, which has a genetic basis, is determined by the specificity of genes expressed by these "complex" neurons. The main goal of the review is to show that the identification of the genes implicated in cognitive functions and the understanding of a functional role of their products is a possible way to overcome covert dualism in neuroscience.

The role of sensory network dynamics in generating a motor program.

Sensory input plays a major role in controlling motor responses during most behavioral tasks. The vestibular organs in the marine mollusk Clione, the statocysts, react to the external environment and continuously adjust the tail and wing motor neurons to keep the animal oriented vertically. However, we suggested previously that during hunting behavior, the intrinsic dynamics of the statocyst network produce a spatiotemporal pattern that may control the motor system independently of environmental cues. Once the response is triggered externally, the collective activation of the statocyst neurons produces a complex sequential signal. In the behavioral context of hunting, such network dynamics may be the main determinant of an intricate spatial behavior. Here, we show that (1) during fictive hunting, the population activity of the statocyst receptors is correlated positively with wing and tail motor output suggesting causality, (2) that fictive hunting can be evoked by electrical stimulation of the statocyst network, and (3) that removal of even a few individual statocyst receptors critically changes the fictive hunting motor pattern. These results indicate that the intrinsic dynamics of a sensory network, even without its normal cues, can organize a motor program vital for the survival of the animal.

Experience-dependent expression of terminal deoxynucleotidyl transferase in mouse brain.

Terminal deoxynucleotidyl transferase (TdT), a template-independent DNA polymerase, contributes to antigen receptor diversity in lymphocytes. Using in situ hybridization, we found that tdt is expressed within neurons of the adult mouse brain. tdt mRNA was localized within pyramidal neurons in the hippocampus, granule and polymorphic cells in the dentate gyrus, Purkinje neurons in the cerebellum, and cortical cells. Increased levels of tdt mRNA in the hippocampus, neocortex, and cerebellum were associated with rearing C57BL/6 mice, but not DBA/2 mice, in enriched environments. Unlike wild types (WT), tdt (-/-) mice did not show improvement in spatial learning and memory as a result of rearing in enriched environments. These results suggest that tdt may be involved in learning and memory saving.

Cellular and network properties in the functioning of the nervous system: from central pattern generators to cognition.

The relation between individual neurons and neuronal networks in performing brain functions is one of the central questions in modern neuroscience. Most of the current literature suggests that the role of individual neurons is negligible and neural networks play a dominant role in the functioning of the nervous system. Individual neurons are usually viewed as network elements whose functions are limited to generating electrical signals and releasing neurotransmitters. Here I summarize experimental evidence that challenges this concept and argue that the unique, intrinsic properties of highly specialized individual neurons are as important for the functioning of the brain as the network properties. I first discuss the studies of relatively 'simple' functions of the nervous system, such as the control of rhythmic 'automatic' movements and generation of circadian rhythm, which indicate that individual neurons may continue performing their functions after being separated from corresponding networks. I then argue that the complex cognitive functions, such as declarative memory, language processing, and face recognition, are likely to be underlain by the properties of groups of highly specialized neurons. These neurons appear to be genetically predisposed to perform cognitive functions and their dysfunctions cannot be compensated by other elements of the nervous system. Under this concept, the electrical signals circulating within and between neural networks are considered to be a means of forming coordinated dynamic ensembles of neurons involved in performing specific functions. While still speculative, this hypothesis may provoke new approaches to studies of neural mechanisms underpinning cognitive functions of the brain.

Winnerless competition between sensory neurons generates chaos: A possible mechanism for molluscan hunting behavior.

In the presence of prey, the marine mollusk Clione limacina exhibits search behavior, i.e., circular motions whose plane and radius change in a chaotic-like manner. We have formulated a dynamical model of the chaotic hunting behavior of Clione based on physiological in vivo and in vitro experiments. The model includes a description of the action of the cerebral hunting interneuron on the receptor neurons of the gravity sensory organ, the statocyst. A network of six receptor model neurons with Lotka-Volterra-type dynamics and nonsymmetric inhibitory interactions has no simple static attractors that correspond to winner take all phenomena. Instead, the winnerless competition induced by the hunting neuron displays hyperchaos with two positive Lyapunov exponents. The origin of the chaos is related to the interaction of two clusters of receptor neurons that are described with two heteroclinic loops in phase space. We hypothesize that the chaotic activity of the receptor neurons can drive the complex behavior of Clione observed during hunting. (c) 2002 American Institute of Physics.