Answering autobiographical questions: the impact of memory and inference on surveys

Survey questions often probe respondents for quantitative facts about events in their past: "During the last 2 weeks, on days when you drank liquor, about how many drinks did you have?" "During the past 12 months, how many visits did you make to a dentist?" "When did you last work at a full-time job?" are all examples from national surveys. Although questions like these make an implicit demand to remember and enumerate specific autobiographical episodes, respondents frequently have trouble complying because of limits on their ability to recall. In these situations, respondents resort to inferences that use partial information from memory to construct a numeric answer. Results from cognitive psychology can be useful in understanding and investigating these phenomena. In particular, cognitive research can help in identifying situations that inhibit or facilitate recall and can reveal inferences that affect the accuracy of respondents' answers.     

Generation of a synthetic memory trace

We investigated the effect of activating a competing, artificially generated, neural representation on encoding of contextual fear memory in mice. We used a c-fos-based transgenic approach to introduce the hM(3)D(q) DREADD receptor (designer receptor exclusively activated by designer drug) into neurons naturally activated by sensory experience. Neural activity could then be specifically and inducibly increased in the hM(3)D(q)-expressing neurons by an exogenous ligand. When an ensemble of neurons for one context (ctxA) was artificially activated during conditioning in a distinct second context (ctxB), mice formed a hybrid memory representation. Reactivation of the artificially stimulated network within the conditioning context was required for retrieval of the memory, and the memory was specific for the spatial pattern of neurons artificially activated during learning. Similar stimulation impaired recall when not part of the initial conditioning.     

A neural mechanism for working and recognition memory in inferior temporal cortex

Inferior temporal (IT) cortex is critical for visual memory, but it is not known how IT neurons retain memories while new information is streaming into the visual system. Single neurons were therefore recorded from IT cortex of two rhesus monkeys performing tasks that required them to hold items in memory while concurrently viewing other items. The neuronal response to an incoming visual stimulus was attenuated if it matched a stimulus actively held in working memory, even when several other stimuli intervened. The neuronal response to novel stimuli declined as the stimuli became familiar to the animal. IT neurons appear to function as adaptive mnemonic "filters" that preferentially pass information about new, unexpected, or not recently seen stimuli.     

Awake hippocampal sharp-wave ripples support spatial memory

The hippocampus is critical for spatial learning and memory. Hippocampal neurons in awake animals exhibit place field activity that encodes current location, as well as sharp-wave ripple (SWR) activity during which representations based on past experiences are often replayed. The relationship between these patterns of activity and the memory functions of the hippocampus is poorly understood. We interrupted awake SWRs in animals learning a spatial alternation task. We observed a specific learning and performance deficit that persisted throughout training. This deficit was associated with awake SWR activity, as SWR interruption left place field activity and post-experience SWR reactivation intact. These results provide a link between awake SWRs and hippocampal memory processes, which suggests that awake replay of memory-related information during SWRs supports learning and memory-guided decision-making.     

Marihuana and memory: acquisition or retrieval?

Two experiments were conducted to determine the means by which marihuana affects human memory. The results of these studies indicated that marihuana did not affect retrieval of information in memory when the method of free recall was used, but did affect recognition processes such that subjects were less able to discriminate between items that had been presented previously and items that had not appeared a short time before. With respect to initial learning, marihuana was shown to affect acquisition processes involved in the storage of information.     

Hippocampal place fields emerge upon single-cell manipulation of excitability during behavior

The origin of the spatial receptive fields of hippocampal place cells has not been established. A hippocampal CA1 pyramidal cell receives thousands of synaptic inputs, mostly from other spatially tuned neurons; however, how the postsynaptic neuron's cellular properties determine the response to these inputs during behavior is unknown. We discovered that, contrary to expectations from basic models of place cells and neuronal integration, a small, spatially uniform depolarization of the spatially untuned somatic membrane potential of a silent cell leads to the sudden and reversible emergence of a spatially tuned subthreshold response and place-field spiking. Such gating of inputs by postsynaptic neuronal excitability reveals a cellular mechanism for receptive field origin and may be critical for the formation of hippocampal memory representations.     

Maintenance of serological memory by polyclonal activation of human memory B cells

Production of antibodies can last for a lifetime, through mechanisms that remain poorly understood. Here, we show that human memory B lymphocytes proliferate and differentiate into plasma cells in response to polyclonal stimuli, such as bystander T cell help and CpG DNA. Furthermore, plasma cells secreting antibodies to recall antigens are produced in vivo at levels proportional to the frequency of specific memory B cells, even several years after antigenic stimulation. Although antigen boosting leads to a transient increase in specific antibody levels, ongoing polyclonal activation of memory B cells offers a means to maintain serological memory for a human lifetime.     

Internally generated cell assembly sequences in the rat hippocampus

A long-standing conjecture in neuroscience is that aspects of cognition depend on the brain's ability to self-generate sequential neuronal activity. We found that reliably and continually changing cell assemblies in the rat hippocampus appeared not only during spatial navigation but also in the absence of changing environmental or body-derived inputs. During the delay period of a memory task, each moment in time was characterized by the activity of a particular assembly of neurons. Identical initial conditions triggered a similar assembly sequence, whereas different conditions gave rise to different sequences, thereby predicting behavioral choices, including errors. Such sequences were not formed in control (nonmemory) tasks. We hypothesize that neuronal representations, evolved for encoding distance in spatial navigation, also support episodic recall and the planning of action sequences.     

Localization of a stable neural correlate of associative memory

Do learning and retrieval of a memory activate the same neurons? Does the number of reactivated neurons correlate with memory strength? We developed a transgenic mouse that enables the long-lasting genetic tagging of c-fos-active neurons. We found neurons in the basolateral amygdala that are activated during Pavlovian fear conditioning and are reactivated during memory retrieval. The number of reactivated neurons correlated positively with the behavioral expression of the fear memory, indicating a stable neural correlate of associative memory. The ability to manipulate these neurons genetically should allow a more precise dissection of the molecular mechanisms of memory encoding within a distributed neuronal network.     

Unsupervised natural experience rapidly alters invariant object representation in visual cortex

Object recognition is challenging because each object produces myriad retinal images. Responses of neurons from the inferior temporal cortex (IT) are selective to different objects, yet tolerant ("invariant") to changes in object position, scale, and pose. How does the brain construct this neuronal tolerance? We report a form of neuronal learning that suggests the underlying solution. Targeted alteration of the natural temporal contiguity of visual experience caused specific changes in IT position tolerance. This unsupervised temporal slowness learning (UTL) was substantial, increased with experience, and was significant in single IT neurons after just 1 hour. Together with previous theoretical work and human object perception experiments, we speculate that UTL may reflect the mechanism by which the visual stream builds and maintains tolerant object representations.     

Category-specific cortical activity precedes retrieval during memory search

Here we describe a functional magnetic resonance imaging study of humans engaged in memory search during a free recall task. Patterns of cortical activity associated with the study of three categories of pictures (faces, locations, and objects) were identified by a pattern-classification algorithm. The algorithm was used to track the reappearance of these activity patterns during the recall period. The reappearance of a given category's activity pattern correlates with verbal recalls made from that category and precedes the recall event by several seconds. This result is consistent with the hypothesis that category-specific activity is cueing the memory system to retrieve studied items.     

Odor cues during slow-wave sleep prompt declarative memory consolidation

Sleep facilitates memory consolidation. A widely held model assumes that this is because newly encoded memories undergo covert reactivation during sleep. We cued new memories in humans during sleep by presenting an odor that had been presented as context during prior learning, and so showed that reactivation indeed causes memory consolidation during sleep. Re-exposure to the odor during slow-wave sleep (SWS) improved the retention of hippocampus-dependent declarative memories but not of hippocampus-independent procedural memories. Odor re-exposure was ineffective during rapid eye movement sleep or wakefulness or when the odor had been omitted during prior learning. Concurring with these findings, functional magnetic resonance imaging revealed significant hippocampal activation in response to odor re-exposure during SWS.     

Selective attention from voluntary control of neurons in prefrontal cortex

Animals can learn to voluntarily control neuronal activity within various brain areas through operant conditioning, but the relevance of that control to cognitive functions is unknown. We found that rhesus monkeys can control the activity of neurons within the frontal eye field (FEF), an oculomotor area of the prefrontal cortex. However, operantly driven FEF activity was primarily associated with selective visual attention, and not oculomotor preparation. Attentional effects were untrained and were observed both behaviorally and neurophysiologically. Furthermore, selective attention correlated with voluntary, but not spontaneous, fluctuations in FEF activity. Our results reveal a specific association of voluntarily driven neuronal activity with "top-down" attention and suggest a basis for the use of neurofeedback training to treat disorders of attention.     

Cell recognition during neuronal development

Insect embryos, with their relatively simple nervous systems, provide a model system with which to study the cellular and molecular mechanisms underlying cell recognition during neuronal development. Such an approach can take advantage of the accessible cells of the grasshopper embryo and the accessible genes of Drosophila. The growth cones of identified neurons express selective affinities for specific axonal surfaces; such specificities give rise to the stereotyped patterns of selective fasciculation common to both species. These and other results suggest that early in development cell lineage and cell interactions lead to the differential expression of cell recognition molecules on the surfaces of small subsets of embryonic neurons whose axons selectively fasciculate with one another. Monoclonal antibodies reveal surface molecules in the Drosophila embryo whose expression correlates with this prediction. It should now be possible to isolate the genes encoding these potential cell recognition molecules and to test their function through the use of molecular genetic approaches in Drosophila.     

Neuronal competition and selection during memory formation

Competition between neurons is necessary for refining neural circuits during development and may be important for selecting the neurons that participate in encoding memories in the adult brain. To examine neuronal competition during memory formation, we conducted experiments with mice in which we manipulated the function of CREB (adenosine 3',5'-monophosphate response element-binding protein) in subsets of neurons. Changes in CREB function influenced the probability that individual lateral amygdala neurons were recruited into a fear memory trace. Our results suggest a competitive model underlying memory formation, in which eligible neurons are selected to participate in amemorytrace as a function of their relative CREB activity at the time of learning.     

Selectivity for 3D shape that reveals distinct areas within macaque inferior temporal cortex

The anterior part of the macaque inferior temporal cortex, area TE, occupies a large portion of the temporal lobe and is critical for object recognition. Thus far, no relation between anatomical subdivisions of TE and neuronal selectivity has been described. Here, we present evidence that neurons selective for three-dimensional (3D) shape are concentrated in the lower bank of the superior temporal sulcus, whereas neurons in lateral TE are generally unselective for 3D shape, though equally selective for 2D shape. These findings reveal that TE consists of at least two distinct areas, one of which processes a specific object property.     

Neurotoxicity of a fragment of the amyloid precursor associated with Alzheimer's disease

Amyloid deposition in senile plaques and the cerebral vasculature is a marker of Alzheimer's disease. Whether amyloid itself contributes to the neurodegenerative process or is simply a by-product of that process is unknown. Pheochromocytoma (PC12) and fibroblast (NIH 3T3) cell lines were transfected with portions of the gene for the human amyloid precursor protein. Stable PC12 cell transfectants expressing a specific amyloid-containing fragment of the precursor protein gradually degenerated when induced to differentiate into neuronal cells with nerve growth factor. Conditioned medium from these cells was toxic to neurons in primary hippocampal cultures, and the toxic agent could be removed by immunoabsorption with an antibody directed against the amyloid polypeptide. Thus, a peptide derived from the amyloid precursor may be neurotoxic.     

Single neurons in the monkey hippocampus and learning of new associations

The medial temporal lobe is crucial for the ability to learn and retain new declarative memories. This form of memory includes the ability to quickly establish novel associations between unrelated items. To better understand the patterns of neural activity during associative memory formation, we recorded the activity of hippocampal neurons of macaque monkeys as they learned new associations. Hippocampal neurons signaled learning by changing their stimulus-selective response properties. This change in the pattern of selective neural activity occurred before, at the same time as, or after learning, which suggests that these neurons are involved in the initial formation of new associative memories.     

Choline acetyltransferase activity in striatum of neonatal rats increased by nerve growth factor

Some neurodegenerative disorders may be caused by abnormal synthesis or utilization of trophic molecules required to support neuronal survival. A test of this hypothesis requires that trophic agents specific for the affected neurons be identified. Cholinergic neurons in the corpus striatum of neonatal rats were found to respond to intracerebroventricular administration of nerve growth factor with prominent, dose-dependent, selective increases in choline acetyltransferase activity. Cholinergic neurons in the basal forebrain also respond to nerve growth factor in this way. These actions of nerve growth factor may indicate its involvement in the normal function of forebrain cholinergic neurons as well as in neurodegenerative disorders involving such cells.