A basic feature of intelligent systems such as the cerebral cortex is the ability to freely associate aspects of perceived experience with an internal representation of the world and make predictions about the future. Here, a hypothesis is presented that the extraordinary performance of the cortex derives from an associative mechanism built in at the cellular level to the basic cortical neuronal unit: the pyramidal cell. The mechanism is robustly triggered by coincident input to opposite poles of the neuron, is exquisitely matched to the large- and fine-scale architecture of the cortex, and is tightly controlled by local microcircuits of inhibitory neurons targeting subcellular compartments. This article explores the experimental evidence and the implications for how the cortex operates.
Synchronised neuronal oscillations at beta frequencies are prevalent in the human motor system, but their function is unclear. In this Opinion article, we propose that the levels of beta oscillations provide a measure of the likelihood that a new voluntary action will need to be actuated. Oscillatory beta activity is in turn modulated by net dopamine levels at sites of cortical input to the basal ganglia. We hypothesise that net dopamine levels are modulated in response to salient internal and external cues. Crucially, the resulting modulation of beta activity is predictive, enabling the appropriate prospective resourcing and preparation of potential actions. Loss of dopamine, as in Parkinson's disease, annuls this function, unless net dopaminergic activity can be elevated through medication.
Neuroelectric oscillations reflect rhythmic shifting of neuronal ensembles between high and low excitability states. In natural settings, important stimuli often occur in rhythmic streams, and when oscillations entrain to an input rhythm their high excitability phases coincide with events in the stream, effectively amplifying neuronal input responses. When operating in a ‘rhythmic mode’, attention can use these differential excitability states as a mechanism of selection by simply enforcing oscillatory entrainment to a task-relevant input stream. When there is no low-frequency rhythm that oscillations can entrain to, attention operates in a ‘continuous mode’, characterized by extended increase in gamma synchrony. We review the evidence for early sensory selection by oscillatory phase-amplitude modulations, its mechanisms and its perceptual and behavioral consequences.
Several theories have proposed possible functions of adult neurogenesis in learning processes on a systems level, such as the avoidance of catastrophic interference and the encoding of temporal and contextual information, and in emotional behavior. Under the assumption of such functionality of new neurons, the question arises: what are the consequences of adult hippocampal neurogenesis beyond the temporally immediate computational benefit? What might provide the evolutionary advantage of maintaining neurogenesis in the dentate gyrus but almost nowhere else? I propose that over the course of life, activity-dependently regulated adult neurogenesis reveals its true significance in the retained ability for lasting and cumulative network adaptations. The hippocampal precursor cells that generate new neurons with their particular acute function represent a ‘neurogenic reserve’: the potential to remain flexible and plastic in hippocampal learning when the individual is exposed to novelty and complexity.
Caspase-3 has been identified as a key mediator of neuronal programmed cell death. This protease plays a central role in the developing nervous system and its activation is observed early in neural tube formation and persists during postnatal differentiation of the neural network. Caspase-3 activation, a crucial event of neuronal cell death program, is also a feature of many chronic neurodegenerative diseases. This traditional apoptotic function of caspase-3 is challenged by recent studies that reveal new cell death-independent roles for mitochondrial-activated caspase-3 in neurite pruning and synaptic plasticity. These findings underscore the need for further research into the mechanism of action and functions of caspase-3 that may prove useful in the development of novel pharmacological treatments for a diverse range of neurological disorders.
LINE-1 (L1) elements are retrotransposons that insert extra copies of themselves throughout the genome using a ‘copy and paste’ mechanism. L1s comprise nearly ∼20% of the human genome and are able to influence chromosome integrity and gene expression upon reinsertion. Recent studies show that L1 elements are active and ‘jumping’ during neuronal differentiation. New somatic L1 insertions could generate ‘genomic plasticity’ in neurons by causing variation in genomic DNA sequences and by altering the transcriptome of individual cells. Thus, L1-induced variation could affect neuronal plasticity and behavior. We discuss potential consequences of L1-induced neuronal diversity and propose that a mechanism for generating diversity in the brain could broaden the spectrum of behavioral phenotypes that can originate from any single genome.
The activation of NMDA receptors (NMDARs) is conditioned by the binding of a co-agonist to a dedicated receptor binding site. It is now largely accepted that D-serine plays this role at many central synapses in the hippocampus, amygdala, hypothalamus, nucleus accumbens, and in prefrontal, visual, and somatosensory cortices. D-Serine has been found to be synthesized, stored, and released by astrocytes ( Figure 1 ). However, several immunolabeling studies and experiments in genetically modified animals have recently led to a suggestion that neurons are primarily responsible for the synthesis and release of D-serine  . Here we argue that such conclusions could have resulted from the erroneous interpretation of experimental data and that they are at odds with a substantial amount of published work.
Invasive recording of dopamine neurons in the substantia nigra and ventral tegmental area (SN/VTA) of behaving animals suggests a role for these neurons in reward learning and novelty processing. In humans, functional magnetic resonance imaging (fMRI) is currently the only non-invasive event-related method to measure SN/VTA activity, but it is debated to what extent fMRI enables inference about dopaminergic responses within the SN/VTA. We consider the anatomical and functional parcellation of the primate SN/VTA and find that its homogeneity suggests little variation in the regional specificity of fMRI signals for reward-related dopaminergic responses. Hence, these responses seem to be well captured by the compound fMRI signal from the SN/VTA, which seems quantitatively related to dopamine release in positron emission tomography (PET). We outline how systematic investigation of the functional parcellation of the SN/VTA in animals, new developments in fMRI analysis and combined PET–fMRI studies can narrow the gap between fMRI and dopaminergic neurotransmission.
One of the most distinguishing features of the adult human brain is the complexity and diversity of its cortical astrocytes. Human protoplasmic astrocytes manifest a threefold larger diameter and have tenfold more primary processes than those of rodents. In all mammals, protoplasmic astrocytes are organized into spatially non-overlapping domains that encompass both neurons and vasculature. Yet unique to humans and primates are additional populations of layer 1 interlaminar astrocytes that extend long (millimeter) fibers, and layer 5–6 polarized astrocytes that also project distinctive long processes. We propose that human cortical evolution has been accompanied by increasing complexity in the form and function of astrocytes, which reflects an expansion of their functional roles in synaptic modulation and cortical circuitry.
Antidepressant treatments enhance plasticity and increase neurogenesis in the adult brain, but it has been unclear how these effects influence mood. We propose that, like environmental enrichment and exercise, antidepressant treatments enhance adaptability by increasing structural variability within the nervous system at many levels, from proliferating precursors to immature synaptic contacts. Conversely, sensory deprivation and chronic stress reduce this structural variability. Activity-dependent competition within the mood-related circuits, guided by rehabilitation, then selects for the survival and stabilization of those structures that best represent the internal or external milieu. Increased variability together with competition-mediated selection facilitates normal function, such as pattern separation within the dentate gyrus and other mood-related circuits, thereby enhancing adaptability toward novel experiences.