Abstract: Our decisions are guided by outcomes that are associated with decisions made in the past. However, the amount of influence each past outcome has on our next decision remains unclear. To ensure optimal decision-making, the weight given to decision outcomes should reflect their salience in predicting future outcomes, and this salience should be modulated by the volatility of the reward environment. We show that human subjects assess volatility in an optimal manner and adjust decision-making accordingly. This optimal estimate of volatility is reflected in the fMRI signal in the anterior cingulate cortex (ACC) when each trial outcome is observed. When a new piece of information is witnessed, activity levels reflect its salience for predicting future outcomes. Furthermore, variations in this ACC signal across the population predict variations in subject learning rates. Our results provide a formal account of how we weigh our different experiences in guiding our future actions.

Abstract: Neuroimaging studies of decision-making have generally related neural activity to objective measures (such as reward magnitude, probability or delay), despite choice preferences being subjective. However, economic theories posit that decision-makers behave as though different options have different subjective values. Here we use functional magnetic resonance imaging to show that neural activity in several brain regions—particularly the ventral striatum, medial prefrontal cortex and posterior cingulate cortex—tracks the revealed subjective value of delayed monetary rewards. This similarity provides unambiguous evidence that the subjective value of potential rewards is explicitly represented in the human brain.

Abstract: Sleep replay of awake experience in the cortex and hippocampus has been proposed to be involved in memory consolidation. However, whether temporally structured replay occurs in the cortex and whether the replay events in the two areas are related are unknown. Here we studied multicell spiking patterns in both the visual cortex and hippocampus during slow-wave sleep in rats. We found that spiking patterns not only in the cortex but also in the hippocampus were organized into frames, defined as periods of stepwise increase in neuronal population activity. The multicell firing sequences evoked by awake experience were replayed during these frames in both regions. Furthermore, replay events in the sensory cortex and hippocampus were coordinated to reflect the same experience. These results imply simultaneous reactivation of coherent memory traces in the cortex and hippocampus during sleep that may contribute to or reflect the result of the memory consolidation process.

Abstract: Nociceptive pain results from the detection of intense or noxious stimuli by specialized high-threshold sensory neurons (nociceptors), a transfer of action potentials to the spinal cord, and onward transmission of the warning signal to the brain. In contrast, clinical pain such as pain after nerve injury (neuropathic pain) is characterized by pain in the absence of a stimulus and reduced nociceptive thresholds so that normally innocuous stimuli produce pain. The development of neuropathic pain involves not only neuronal pathways, but also Schwann cells, satellite cells in the dorsal root ganglia, components of the peripheral immune system, spinal microglia and astrocytes. As we increasingly appreciate that neuropathic pain has many features of a neuroimmune disorder, immunosuppression and blockade of the reciprocal signaling pathways between neuronal and non-neuronal cells offer new opportunities for disease modification and more successful management of pain.

Abstract: Microgliosis is a common response to multiple types of damage in the CNS. However, the origin of the cells involved in this process is still controversial and the relative importance of local expansion versus recruitment of microglia progenitors from the bloodstream is unclear. Here, we investigated the origin of microglia using chimeric animals obtained by parabiosis. We found no evidence of microglia progenitor recruitment from the circulation in denervation or CNS neurodegenerative disease, suggesting that maintenance and local expansion of microglia are solely dependent on the self-renewal of CNS resident cells in these models.

Abstract: Mutations in superoxide dismutase-1 (SOD1) cause a form of the fatal paralytic disorder amyotrophic lateral sclerosis (ALS), presumably by a combination of cell-autonomous and non–cell-autonomous processes. Here, we show that expression of mutated human SOD1 in primary mouse spinal motor neurons does not provoke motor neuron degeneration. Conversely, rodent astrocytes expressing mutated SOD1 kill spinal primary and embryonic mouse stem cell–derived motor neurons. This is triggered by soluble toxic factor(s) through a Bax-dependent mechanism. However, mutant astrocytes do not cause the death of spinal GABAergic or dorsal root ganglion neurons or of embryonic stem cell–derived interneurons. In contrast to astrocytes, fibroblasts, microglia, cortical neurons and myocytes expressing mutated SOD1 do not cause overt neurotoxicity. These findings indicate that astrocytes may play a role in the specific degeneration of spinal motor neurons in ALS. Identification of the astrocyte-derived soluble factor(s) may have far-reaching implications for ALS from both a pathogenic and therapeutic standpoint.

Abstract: The development of new treatments for depression is predicated upon identification of neural substrates and mechanisms that underlie its etiology and pathophysiology. The heterogeneity of depression indicates that its origin may lie in dysfunction of multiple brain regions. Here we evaluate adult hippocampal neurogenesis as a candidate mechanism for the etiology of depression and as a substrate for antidepressant action. Current evidence indicates that adult hippocampal neurogenesis may not be a major contributor to the development of depression, but may be required for some of the behavioral effects of antidepressants. We next revisit the functional differentiation of the hippocampus along the septo-temporal axis within the context of adult hippocampal neurogenesis and suggest that neurogenesis in the ventral dentate gyrus may be preferentially involved in regulation of emotion. Finally, we speculate on how increased adult hippocampal neurogenesis may modulate dentate gyrus function to confer the behavioral effects of antidepressants.

Abstract: We report that temporal spike sequences from hippocampal place neurons of rats on an elevated track recurred in reverse order at the end of a run, but in forward order in anticipation of the run, coinciding with sharp waves. Vector distances between the place fields were reflected in the temporal structure of these sequences. This bidirectional re-enactment of temporal sequences may contribute to the establishment of higher-order associations in episodic memory.

Abstract: The 'neurotrophin hypothesis of depression' is based largely on correlations between stress or antidepressant treatment and down- or upregulation, respectively, of brain-derived neurotrophic factor (BDNF). Genetic disruption of the signaling pathways involving BDNF and its receptor, the tyrosine kinase TrkB, does not seem to cause depressive behaviors, but does hamper the effect of antidepressant drugs. Thus, BDNF may be a target of antidepressants, but not the sole mediator of depression or anxiety. Advances in BDNF cell biology, including its transcription through multiple promoters, trafficking and secretion, may provide new insights into its role in mood disorders. Moreover, as the precursor proBDNF and the mature protein mBDNF can elicit opposite effects on cellular functions, the impact of proBDNF and its cleavage on mood should be considered. Opposing influences of mBDNF and proBDNF on long-term potentiation and long-term depression might contribute to the dichotomy of BDNF actions on behaviors mediated by the brain stress and reward systems.

Abstract: The brain is a heterogeneous organ with regionally varied and constantly changing energetic needs. Blood vessels in the brain are equipped with control mechanisms that match oxygen and glucose delivery through blood flow with the local metabolic demands that are imposed by neural activity. However, the cellular bases of this mechanism have remained elusive. A major advance has been the demonstration that astrocytes, cells with extensive contacts with both synapses and cerebral blood vessels, participate in the increases in flow evoked by synaptic activity. Their organization in nonoverlapping spatial domains indicates that they are uniquely positioned to shape the spatial distribution of the vascular responses that are evoked by neural activity. Astrocytic calcium is an important determinant of microvascular function and may regulate flow independently of synaptic activity. The involvement of astrocytes in neurovascular coupling has broad implications for the interpretation of functional imaging signals and for the understanding of brain diseases that are associated with neurovascular dysfunction.

Abstract: Microglia are crucially important myeloid cells in the CNS and constitute the first immunological barrier against pathogens and environmental insults. The factors controlling microglia recruitment from the blood remain elusive and the direct circulating microglia precursor has not yet been identified in vivo. Using a panel of bone marrow chimeric and adoptive transfer experiments, we found that circulating Ly-6C(hi)CCR2(+) monocytes were preferentially recruited to the lesioned brain and differentiated into microglia. Notably, microglia engraftment in CNS pathologies, which are not associated with overt blood-brain barrier disruption, required previous conditioning of brain (for example, by direct tissue irradiation). Our results identify Ly-6C(hi)CCR2(+) monocytes as direct precursors of microglia in the adult brain and establish the importance of local factors in the adult CNS for microglia engraftment.

Abstract: Dopamine (DA) D1 receptor (D1R) stimulation in prefrontal cortex (PFC) produces an 'inverted-U' dose-response, whereby either too little or too much D1R stimulation impairs spatial working memory. This response has been observed across species, including genetic linkages with human cognitive abilities, PFC activation states and DA synthesis. The cellular basis for the inverted U has long been sought, with in vitro intracellular recordings supporting a variety of potential mechanisms. The current study demonstrates that the D1R agonist inverted-U response can be observed in PFC neurons of behaving monkeys: low levels of D1R stimulation enhance spatial tuning by suppressing responses to nonpreferred directions, whereas high levels reduce delay-related firing for all directions, eroding tuning. These sculpting actions of D1R stimulation are mediated in monkeys and rats by cyclic AMP intracellular signaling. The evidence for an inverted U at the cellular level in behaving animals promises to bridge in vitro molecular analyses with human cognitive experience.

Abstract: The gene encoding the serotonin transporter (5-HTT) contains a regulatory variation that has been associated with anxiety-related traits and susceptibility for depression. Here we highlight recent discoveries related to allelic variation of 5-HTT function with respect to emotion regulation and social behavior, drawing from an interdisciplinary perspective of behavioral genetics and cognitive neuroscience. Following a reductionistic path that leads from gene-behavior association studies to neuroimaging and epigenetic studies, we compare two models of 5-HTT-dependent modulation of brain activity and discuss the role of life stress experience in modifying 5-HTT function in the brain. Integration of these findings suggests that the impact of the 5-HTT gene on behavior is much broader than is commonly appreciated and may have a role in social cognition.

Abstract: Recent decades have witnessed tremendous advances in the neuroscience of emotion, learning and memory, and in animal models for understanding depression and anxiety. This review focuses on new rationally designed psychiatric treatments derived from preclinical human and animal studies. Nonpharmacological treatments that affect disrupted emotion circuits include vagal nerve stimulation, rapid transcranial magnetic stimulation and deep brain stimulation, all borrowed from neurological interventions that attempt to target known pathological foci. Other approaches include drugs that are given in relation to specific learning events to enhance or disrupt endogenous emotional learning processes. Imaging data suggest that common regions of brain activation are targeted with pharmacological and somatic treatments as well as with the emotional learning in psychotherapy. Although many of these approaches are experimental, the rapidly developing understanding of emotional circuit regulation is likely to provide exciting and powerful future treatments for debilitating mood and anxiety disorders.

Abstract: The functions of cortical areas depend on their inputs and outputs, but the detailed circuits made by long-range projections are unknown. We show that the light-gated channel channelrhodopsin-2 (ChR2) is delivered to axons in pyramidal neurons in vivo. In brain slices from ChR2-expressing mice, photostimulation of ChR2-positive axons can be transduced reliably into single action potentials. Combining photostimulation with whole-cell recordings of synaptic currents makes it possible to map circuits between presynaptic neurons, defined by ChR2 expression, and postsynaptic neurons, defined by targeted patching. We applied this technique, ChR2-assisted circuit mapping (CRACM), to map long-range callosal projections from layer (L) 2/3 of the somatosensory cortex. L2/3 axons connect with neurons in L5, L2/3 and L6, but not L4, in both ipsilateral and contralateral cortex. In both hemispheres the L2/3-to-L5 projection is stronger than the L2/3-to-L2/3 projection. Our results suggest that laminar specificity may be identical for local and long-range cortical projections.

Abstract: Music and speech are very cognitively demanding auditory phenomena generally attributed to cortical rather than subcortical circuitry. We examined brainstem encoding of linguistic pitch and found that musicians show more robust and faithful encoding compared with nonmusicians. These results not only implicate a common subcortical manifestation for two presumed cortical functions, but also a possible reciprocity of corticofugal speech and music tuning, providing neurophysiological explanations for musicians' higher language-learning ability.

Abstract: Throughout adulthood, new neurons are continuously added to the dentate gyrus, a hippocampal subregion that is important in spatial learning. Whether these adult-generated granule cells become functionally integrated into memory networks is not known. We used immunohistochemical approaches to visualize the recruitment of new neurons into circuits supporting water maze memory in intact mice. We show that as new granule cells mature, they are increasingly likely to be incorporated into circuits supporting spatial memory. By the time the cells are 4 or more weeks of age, they are more likely than existing granule cells to be recruited into circuits supporting spatial memory. This preferential recruitment supports the idea that new neurons make a unique contribution to memory processing in the dentate gyrus.

Abstract: Recognition molecules of the immunoglobulin superfamily have important roles in neuronal interactions during ontogeny, including migration, survival, axon guidance and synaptic targeting. Their downstream signal transduction events specify whether a cell changes its place of residence or projects axons and dendrites to targets in the brain, allowing the construction of a dynamic neural network. A wealth of recent discoveries shows that cell adhesion molecules interact with attractant and repellent guidance receptors to control growth cone and cell motility in a coordinate fashion. We focus on the best-studied subclasses, the neural cell adhesion molecule NCAM and the L1 family of adhesion molecules, which share important structural and functional features. We have chosen these paradigmatic molecules and their interactions with other recognition molecules as instructive for elucidating the mechanisms by which other recognition molecules may guide cell interactions during development or modify their function as a result of injury, learning and memory.

Abstract: Here we report an in vitro model system for studying the molecular and cellular mechanisms that underlie the neurodegenerative disease amyotrophic lateral sclerosis (ALS). Embryonic stem cells (ESCs) derived from mice carrying normal or mutant transgenic alleles of the human SOD1 gene were used to generate motor neurons by in vitro differentiation. These motor neurons could be maintained in long-term coculture either with additional cells that arose during differentiation or with primary glial cells. Motor neurons carrying either the nonpathological human SOD1 transgene or the mutant SOD1G93A allele showed neurodegenerative properties when cocultured with SOD1G93A glial cells. Thus, our studies demonstrate that glial cells carrying a human SOD1G93A mutation have a direct, non–cell autonomous effect on motor neuron survival. More generally, our results show that ESC-based models of disease provide a powerful tool for studying the mechanisms of neural degeneration. These phenotypes displayed in culture could provide cell-based assays for the identification of new ALS drugs.

Abstract: The release of transmitters from glia influences synaptic functions. The modalities and physiological functions of glial release are poorly understood. Here we show that glutamate exocytosis from astrocytes of the rat hippocampal dentate molecular layer enhances synaptic strength at excitatory synapses between perforant path afferents and granule cells. The effect is mediated by ifenprodil-sensitive NMDA ionotropic glutamate receptors and involves an increase of transmitter release at the synapse. Correspondingly, we identify NMDA receptor 2B subunits on the extrasynaptic portion of excitatory nerve terminals. The receptor distribution is spatially related to glutamate-containing synaptic-like microvesicles in the apposed astrocytic processes. This glial regulatory pathway is endogenously activated by neuronal activity-dependent stimulation of purinergic P2Y1 receptors on the astrocytes. Thus, we provide the first combined functional and ultrastructural evidence for a physiological control of synaptic activity via exocytosis of glutamate from astrocytes.

Abstract: The ability to predict favorable outcomes using environmental cues is an essential part of learned behavior. Dopamine neurons in the midbrain encode such stimulus-reward relationships in a manner consistent with contemporary learning models, but it is unclear how encoding this translates into actual dopamine release in target regions. Here, we sampled dopamine levels in the rat nucleus accumbens on a rapid (100 ms) timescale using electrochemical technology during a classical conditioning procedure. Early in conditioning, transient dopamine-release events signaled a primary reward, but not predictive cues. After repeated cue-reward pairings, dopamine signals shifted in time to predictive cue onset and were no longer observed at reward delivery. In the absence of stimulus-reward conditioning, there was no shift in the dopamine signal. Consistent with proposed roles in reward prediction and incentive salience, these results indicate that rapid dopamine release provides a reward signal that is dynamically modified by associative learning.

Abstract: Evidence indicates that sleep after learning is critical for the subsequent consolidation of human memory. Whether sleep before learning is equally essential for the initial formation of new memories, however, remains an open question. We report that a single night of sleep deprivation produces a significant deficit in hippocampal activity during episodic memory encoding, resulting in worse subsequent retention. Furthermore, these hippocampal impairments instantiate a different pattern of functional connectivity in basic alertness networks of the brainstem and thalamus. We also find that unique prefrontal regions predict the success of encoding for sleep-deprived individuals relative to those who have slept normally. These results demonstrate that an absence of prior sleep substantially compromises the neural and behavioral capacity for committing new experiences to memory. It therefore appears that sleep before learning is critical in preparing the human brain for next-day memory formation—a worrying finding considering society's increasing erosion of sleep time.

Abstract: The firing pattern of entorhinal 'grid cells' is thought to provide an intrinsic metric for space. We report a strong experience-dependent environmental influence: the spatial scales of the grids (which are aligned and have fixed relative sizes within each animal) vary parametrically with changes to a familiar environment's size and shape. Thus grid scale reflects an interaction between intrinsic, path-integrative calculation of location and learned associations to the external environment.

Abstract: Research across species highlights the critical role of the amygdala in fear conditioning. However, fear conditioning, involving direct aversive experience, is only one means by which fears can be acquired. Exploiting aversive experiences of other individuals through social fear learning is less risky. Behavioral research provides important insights into the workings of social fear learning, and the neural mechanisms are beginning to be understood. We review research suggesting that an amygdala-centered model of fear conditioning can help to explain social learning of fear through observation and instruction. We also describe how observational and instructed fear is distinguished by involvement of additional neural systems implicated in social-emotional behavior, language and explicit memory, and propose a modified conditioning model to account for social fear learning. A better understanding of social fear learning promotes integration of biological principles of learning with cultural evolution.

Abstract: Although new and functional neurons are produced in the adult brain, little is known about how they integrate into mature networks. Here we explored the mechanisms of synaptogenesis on neurons born in the adult mouse hippocampus using confocal microscopy, electron microscopy and live imaging. We report that new neurons, similar to mature granule neurons, were contacted by axosomatic, axodendritic and axospinous synapses. Consistent with their putative role in synaptogenesis, dendritic filopodia were more abundant during the early stages of maturation and, when analyzed in three dimensions, the tips of all filopodia were found within 200 nm of preexisting boutons that already synapsed on other neurons. Furthermore, dendritic spines primarily synapsed on multiple-synapse boutons, suggesting that initial contacts were preferentially made with preexisting boutons already involved in a synapse. The connectivity of new neurons continued to change until at least 2 months, long after the formation of the first dendritic protrusions.

Abstract: Although endocannabinoids constitute one of the first lines of defense against pain, the anatomical locus and the precise receptor mechanisms underlying cannabinergic modulation of pain are uncertain. Clinical exploitation of the system is severely hindered by the cognitive deficits, memory impairment, motor disturbances and psychotropic effects resulting from the central actions of cannabinoids. We deleted the type 1 cannabinoid receptor (CB1) specifically in nociceptive neurons localized in the peripheral nervous system of mice, preserving its expression in the CNS, and analyzed these genetically modified mice in preclinical models of inflammatory and neuropathic pain. The nociceptor-specific loss of CB1 substantially reduced the analgesia produced by local and systemic, but not intrathecal, delivery of cannabinoids. We conclude that the contribution of CB1-type receptors expressed on the peripheral terminals of nociceptors to cannabinoid-induced analgesia is paramount, which should enable the development of peripherally acting CB1 analgesic agonists without any central side effects.

Abstract: Brain ischemia results from cardiac arrest, stroke or head trauma. These conditions can cause severe brain damage and are a leading cause of death and long-term disability. Neurons are far more susceptible to ischemic damage than neighboring astrocytes, but astrocytes have diverse and important functions in many aspects of ischemic brain damage. Here we review three main roles of astrocytes in ischemic brain damage. First, we consider astrocyte glycogen stores, which can defend the brain against hypoglycemic brain damage but may aggravate brain damage during ischemia due to enhanced lactic acidosis. Second, we review recent breakthroughs in understanding astrocytic mechanisms of transmitter release, particularly for those transmitters with known roles in ischemic brain damage: glutamate, D-serine, ATP and adenosine. Third, we discuss the role of gap-junctionally connected networks of astrocytes in mediating the spread of damaging molecules to healthy 'bystanders' during infarct expansion in stroke.

Abstract: High-level visual cortex in humans includes functionally defined regions that preferentially respond to objects, faces and places. It is unknown how these regions develop and whether their development relates to recognition memory. We used functional magnetic resonance imaging to examine the development of several functionally defined regions including object (lateral occipital complex, LOC)-, face (‘fusiform face area’, FFA; superior temporal sulcus, STS)- and place (‘parahippocampal place area’, PPA)-selective cortices in children (ages 7‐11), adolescents (12‐16) and adults. Right FFA and left PPA volumes were substantially larger in adults than in children. This development occurred by expansion of FFA and PPA into surrounding cortex and was correlated with improved recognition memory for faces and places, respectively. In contrast, LOC and STS volumes and object-recognition memory remained constant across ages. Thus, the ventral stream undergoes a prolonged maturation that varies temporally across functional regions, is determined by brain region rather than stimulus category, and is correlated with the development of category-specific recognition memory.

Abstract: Ts65Dn mice, a model for Down syndrome, have excessive inhibition in the dentate gyrus, a condition that could compromise synaptic plasticity and mnemonic processing. We show that chronic systemic treatment of these mice with GABAA antagonists at non-epileptic doses causes a persistent post-drug recovery of cognition and long-term potentiation. These results suggest that over-inhibition contributes to intellectual disabilities associated with Down syndrome and that GABAA antagonists may be useful therapeutic agents for this disorder.