Schema-dependent gene activation and memory encoding in neocortex

When new learning occurs against the background of established prior knowledge, relevant new information can be assimilated into a schema and thereby expand the knowledge base. An animal model of this important component of memory consolidation reveals that systems memory consolidation can be very fast. In experiments with rats, we found that the hippocampal-dependent learning of new paired associates is associated with a striking up-regulation of immediate early genes in the prelimbic region of the medial prefrontal cortex, and that pharmacological interventions targeted at that area can prevent both new learning and the recall of remotely and even recently consolidated information. These findings challenge the concept of distinct fast (hippocampal) and slow (cortical) learning systems, and shed new light on the neural mechanisms of memory assimilation into schemas.     

Enhancement of consolidated long-term memory by overexpression of protein kinase Mzeta in the neocortex

Memories are more easily disrupted than improved. Many agents can impair memories during encoding and consolidation. In contrast, the armamentarium of potential memory enhancers is so far rather modest. Moreover, the effect of the latter appears to be limited to enhancing new memories during encoding and the initial period of cellular consolidation, which can last from a few minutes to hours after learning. Here, we report that overexpression in the rat neocortex of the protein kinase C isozyme protein kinase Mζ (PKMζ) enhances long-term memory, whereas a dominant negative PKMζ disrupts memory, even long after memory has been formed.     

Short-term memory, parsing, and the primate frontal cortex

Removal of the frontal cortex of primates resulted earlier in a psychological deficit usually classified in terms of short-term memory. This classification is based on impairment in performance of delayed-response or alternation-type tasks. We report an experiment in which the classical 5-seconddelay right-left-right-left (R-L-R-L) altenation task was modified by placing a 15-seconid interval between each R-L couplet: R-L . . . R-L . . . R-L . . . . This mnodification made it possible for monkeys with frontal lesions, which had failed the classical task, to perform with very few errors. The result suggests that proper division, parsing of the stream of stimuli to which the organism is subjected, is a more important variable in the mechanism of short-term memory than is the maintenance of a neural trace per se.     

Retrograde amnesia produced by electroconvulsive shock after reactivation of a consolidated memory trace

Rats had a memory loss of a fear response when they received an electroconvulsive shock 24 hours after the fear-conditioning trial and preceded by a brief presentation of the conditioned stimulus. No such loss occurred when the conditioned stimulus was not presented. The memory loss in animals given electroconvulsive shock 24 hours after conditioning was, furthermore, as great as that displayed in animals given electroconvulsive shock immediately after conditioning. This result throws doubt on the assertion that electroconvulsive shock exerts a selective amnesic effect on recently acquired memories and thus that electroconvulsive shock produces amnesia solely through interference with memory trace consolidation.     

The primate hippocampal formation: evidence for a time-limited role in memory storage

Clinical and experimental studies have shown that the hippocampal formation and related structures in the medial temporal lobe are important for learning and memory. Retrograde amnesia was studied prospectively in monkeys to understand the contribution of the hippocampal formation to memory function. Monkeys learned to discriminate 100 pairs of objects beginning 16, 12, 8, 4, and 2 weeks before the hippocampal formation was removed (20 different pairs at each time period). Two weeks after surgery, memory was assessed by presenting each of the 100 object pairs again for a single-choice trial. Normal monkeys exhibited forgetting; that is, they remembered recently learned objects better than objects learned many weeks earlier. Monkeys with hippocampal damage were severely impaired at remembering recently learned objects. In addition, they remembered objects learned long ago as well as normal monkeys did and significantly better than they remembered objects learned recently. These results show that the hippocampal formation is required for memory storage for only a limited period of time after learning. As time passes, its role in memory diminishes, and a more permanent memory gradually develops independently of the hippocampal formation, probably in neocortex.     

Learning-induced LTP in neocortex

The hypothesis that learning occurs through long-term potentiation (LTP)- and long-term depression (LTD)-like mechanisms is widely held but unproven. This hypothesis makes three assumptions: Synapses are modifiable, they modify with learning, and they strengthen through an LTP-like mechanism. We previously established the ability for synaptic modification and a synaptic strengthening with motor skill learning in horizontal connections of the rat motor cortex (MI). Here we investigated whether learning strengthened these connections through LTP. We demonstrated that synapses in the trained MI were near the ceiling of their modification range, compared with the untrained MI, but the range of synaptic modification was not affected by learning. In the trained MI, LTP was markedly reduced and LTD was enhanced. These results are consistent with the use of LTP to strengthen synapses during learning.     

Clusters of coupled neuroblasts in embryonic neocortex.

The neocortex of the brain develops from a simple germinal layer into a complex multilayer structure. To investigate cellular interactions during early neocortical development, whole-cell patch clamp recordings were made from neuroblasts in the ventricular zone of fetal rats. During early corticogenesis, neuroblasts are physiologically coupled by gap junctions into clusters of 15 to 90 cells. The coupled cells form columns within the ventricular zone and, by virtue of their membership in clusters, have low apparent membrane resistances and generate large responses to the inhibitory neurotransmitter gamma-aminobutyric acid. As neuronal migration out of the ventricular zone progresses, the number of cells within the clusters decreases. These clusters allow direct cell to cell interaction at the earliest stages of corticogenesis.     

Stereotyped position of local synaptic targets in neocortex

The microcircuitry of the mammalian neocortex remains largely unknown. Although the neocortex could be composed of scores of precise circuits, an alternative possibility is that local connectivity is probabilistic or even random. To examine the precision and degree of determinism in the neocortical microcircuitry, we used optical probing to reconstruct microcircuits in layer 5 from mouse primary visual cortex. We stimulated "trigger" cells, isolated from a homogenous population of corticotectal pyramidal neurons, while optically detecting "follower" neurons directly driven by the triggers. Followers belonged to a few selective anatomical classes with stereotyped physiological and synaptic responses. Moreover, even the position of the followers appeared determined across animals. Our data reveal precisely organized cortical microcircuits.     

Cell cycle dependence of laminar determination in developing neocortex

The neocortex is patterned in layers of neurons that are generated in an orderly sequence during development. This correlation between cell birthday and laminar fate prompted an examination of how neuronal phenotypes are determined in the developing cortex. At various times after labeling with [3H]thymidine, embryonic progenitor cells were transplanted into older host brains. The laminar fate of transplanted neurons correlates with the position of their progenitors in the cell cycle at the time of transplantation. Daughters of cells transplanted in S-phase migrate to layer 2/3, as do host neurons. Progenitors transplanted later in the cell cycle, however, produce daughters that are committed to their normal, deep-layer fates. Thus, environmental factors are important determinants of laminar fate, but embryonic progenitors undergo cyclical changes in their ability to respond to such cues.     

Clonal production and organization of inhibitory interneurons in the neocortex

The neocortex contains excitatory neurons and inhibitory interneurons. Clones of neocortical excitatory neurons originating from the same progenitor cell are spatially organized and contribute to the formation of functional microcircuits. In contrast, relatively little is known about the production and organization of neocortical inhibitory interneurons. We found that neocortical inhibitory interneurons were produced as spatially organized clonal units in the developing ventral telencephalon. Furthermore, clonally related interneurons did not randomly disperse but formed spatially isolated clusters in the neocortex. Individual clonal clusters consisting of interneurons expressing the same or distinct neurochemical markers exhibited clear vertical or horizontal organization. These results suggest that the lineage relationship plays a pivotal role in the organization of inhibitory interneurons in the neocortex.     

Identified sources and targets of slow inhibition in the neocortex

There are two types of inhibitory postsynaptic potentials in the cerebral cortex. Fast inhibition is mediated by ionotropic gamma-aminobutyric acid type A (GABA(A)) receptors, and slow inhibition is due to metabotropic GABA(B) receptors. Several neuron classes elicit inhibitory postsynaptic potentials through GABA(A) receptors, but possible distinct sources of slow inhibition remain unknown. We identified a class of GABAergic interneurons, the neurogliaform cells, that, in contrast to other GABA-releasing cells, elicited combined GABA(A) and GABA(B) receptor-mediated responses with single action potentials and that predominantly targeted the dendritic spines of pyramidal neurons. Slow inhibition evoked by a distinct interneuron in spatially restricted postsynaptic compartments could locally and selectively modulate cortical excitability.     

Social components of fitness in primate groups

There is much interest in the evolutionary forces that favored the evolution of large brains in the primate order. The social brain hypothesis posits that selection has favored larger brains and more complex cognitive capacities as a means to cope with the challenges of social life. The hypothesis is supported by evidence that shows that group size is linked to various measures of brain size. But it has not been clear how cognitive complexity confers fitness advantages on individuals. Research in the field and laboratory shows that sophisticated social cognition underlies social behavior in primate groups. Moreover, a growing body of evidence suggests that the quality of social relationships has measurable fitness consequences for individuals.     

Ongoing in vivo experience triggers synaptic metaplasticity in the neocortex

In vivo experience can occlude subsequent induction of long-term potentiation and enhance long-term depression of synaptic responses. Although a reduced capacity for synaptic strengthening may function to prevent excessive excitation, such an effect paradoxically implies that continued experience or training should not improve and may even degrade neural representations. In mice, we examined the effect of ongoing whisker stimulation on synaptic strengthening at layer 4-2/3 synapses in the barrel cortex. Although N-methyl-d-aspartate receptors were required to initiate strengthening, they subsequently suppressed further potentiation at these synapses in vitro and in vivo. Despite this transition, synaptic strengthening continued with additional sensory activity but instead required the activation of metabotropic glutamate receptors, suggesting a mechanism by which continued experience can result in increasing synaptic strength over time.     

Neural basis of orientation perception in primate vision

Orientational differences in human visual acuity can be related parametrically to the distribution of optimal orientations for the receptive fields of neurons in the striate cortex of the rhesus monkey. Both behavioral measures of acuity and the distribution of receptive fields exhibit maximums for stimuli horizontal or vertical relative to the retina; the effect diminishes with distance from the fovea. The anisotropy in the neuronal population and in visual acuity appear to be determined by postnatal visual experience.