Explore the vast range of titles available.

Understanding the molecular and cellular changes that underlie memory, the engram, requires the identification, isolation and manipulation of the neurons involved. This presents a major difficulty for complex forms of memory, for example hippocampus-dependent declarative memory, where the participating neurons are likely to be sparse, anatomically distributed and unique to each individual brain and learning event. In this paper, I discuss several new approaches to this problem. In vivo calcium imaging techniques provide a means of assessing the activity patterns of large numbers of neurons over long periods of time with precise anatomical identification. This provides important insight into how the brain represents complex information and how this is altered with learning. The development of techniques for the genetic modification of neural ensembles based on their natural, sensory-evoked, activity along with optogenetics allows direct tests of the coding function of these ensembles. These approaches provide a new methodological framework in which to examine the mechanisms of complex forms of learning at the level of the neurons involved in a specific memory.

Empathy is an important psychological capacity that involves the ability to recognize and share emotions with others. In humans, empathy for others is facilitated by having had a similar prior experience. It increases with the intensity of distress that observers believe is occurring to others, and is associated with acute emotional responses to witnessing others' distress. We sought to develop a relatively simple and fast mouse model of human empathy that resembled these characteristics. We modeled empathy by measuring the freezing of observer mice to observing the footshock of a subject mouse. Observer mice froze to subject footshocks only when they had a similar shock experience 24 hours earlier. Moreover, this freezing increased with the number of footshocks given to the subject and it was accentuated within seconds after footshock delivery. Freezing was not seen in naïve observers or in experienced observers that observed a subject who was spared footshock. Observers did not freeze to a subject's footshock when they had experienced a swim stress 24 hours prior, demonstrating a specific effect for shared experience, as opposed to a generalized stressor in eliciting observer mouse freezing. We propose that this two-day experimental protocol resembles many aspects of human empathy in a mouse model that is amenable to transgenic analysis of neural substrates for empathy and its impairment in certain clinical disorders.

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.

Synaptic inputs on dendrites are nonlinearly converted to action potential outputs, yet the spatiotemporal patterns of dendritic activation remain to be elucidated at single-synapse resolution. In rodents, we optically imaged synaptic activities from hundreds of dendritic spines in hippocampal and neocortical pyramidal neurons ex vivo and in vivo. Adjacent spines were frequently synchronized in spontaneously active networks, thereby forming dendritic foci that received locally convergent inputs from presynaptic cell assemblies. This precise subcellular geometry manifested itself during N-methyl-D-aspartate receptor-dependent circuit remodeling. Thus, clustered synaptic plasticity is innately programmed to compartmentalize correlated inputs along dendrites and may reify nonlinear synaptic integration.

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 hM₃D 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 hM₃D 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.

The hippocampus is critical for episodic memory and computational studies have predicted specific functions for each hippocampal subregion. Particularly, the dentate gyrus (DG) is hypothesized to perform pattern separation by forming distinct representations of similar inputs. How pattern separation is achieved by the DG remains largely unclear. By examining neuronal activities at a population level, we revealed that, unlike CA1 neuron populations, dentate granule cell (DGC) ensembles activated by learning were not preferentially reactivated by memory recall. Moreover, when mice encountered an environment to which they had not been previously exposed, a novel DGC population—rather than the previously activated DGC ensembles that responded to past events—was selected to represent the new environmental inputs. This selection of a novel responsive DGC population could be triggered by small changes in environmental inputs. Therefore, selecting distinct DGC populations to represent similar but not identical inputs is a mechanism for pattern separation. Being able to keep memories of similar events separate in your mind is an essential part of remembering. If you use the same carpark every day, recalling where you left your car this morning is challenging, not because you have to remember an event from long ago, but because you have to distinguish between many similar memories. Keeping memories distinct is one of the functions of a subregion of the hippocampus called the dentate gyrus. The process of taking complex memories and converting them into representations that are less easily confused is known as pattern separation. Exactly how the dentate gyrus achieves this, however, is unclear. Computational models predict that a different population of dentate gyrus cells will be active when an animal is in different environments. However, previous experiments have instead shown that the same population of cells is active in multiple environments, and that cells distinguish between environments by firing at different rates. Now, Deng et al. have added to our understanding of pattern separation. The researchers used a type of genetically modified mouse in which it is possible to identify or ‘tag' the activity of a population of hippocampal neurons at multiple time points. They placed each mouse in a box and noted which hippocampal neurons were active as the animal learned about its new environment. After several such learning episodes, the animal received a mild electric shock inside the box. When it was returned to the box the next day, the mouse remembered receiving the shock, enabling the researchers to note which neurons were active during the retrieval process. Deng et al. found that in a subregion of the hippocampus called CA1, the particular neurons that were active during the initial learning episode were also likely to be active when the animals remembered receiving the shock. However, this was not the case for the dentate gyrus: in this subregion, distinct groups of cells were active during learning and during retrieval. Moreover, exposing the mice to two subtly different environments activated two distinct groups of cells in the dentate gyrus. The work of Deng et al. reveals that memory retrieval does not always involve reactivation of the same neurons that were active during encoding. More importantly, the results indicate that the dentate gyrus performs pattern separation by using distinct populations of cells to represent similar but non-identical memories. Overall the findings add to our understanding of the mechanisms that underpin memory formation.

Conflicting evidence exists regarding the role of infralimbic cortex (IL) in the environmental control of appetitive behavior. Inhibition of IL, irrespective of its intrinsic neural activity, attenuates not only the ability of environmental cues predictive of reward availability to promote reward seeking, but also the ability of environmental cues predictive of reward omission to suppress this behavior. Here we report that such bidirectional behavioral modulation in rats is mediated by functionally distinct units of neurons (neural ensembles) that are concurrently localized within the same IL brain area but selectively reactive to different environmental cues. Ensemble-specific neural activity is thought to function as a memory engram representing a learned association between environment and behavior. Our findings establish the causal evidence for the concurrent existence of two distinct engrams within a single brain site, each mediating opposing environmental actions on a learned behavior.

Neuregulin-1 (NRG1) and its ErbB2/B4 receptors are encoded by candidate susceptibility genes for schizophrenia, yet the essential functions of NRG1 signaling in the CNS are still unclear. Using CRE/LOX technology, we have inactivated ErbB2/B4-mediated NRG1 signaling specifically in the CNS. In contrast to expectations, cell layers in the cerebral cortex, hippocampus, and cerebellum develop normally in the mutant mice. Instead, loss of ErbB2/B4 impairs dendritic spine maturation and perturbs interactions of postsynaptic scaffold proteins with glutamate receptors. Conversely, increased NRG1 levels promote spine maturation. ErbB2/B4-deficient mice show increased aggression and reduced prepulse inhibition. Treatment with the antipsychotic drug clozapine reverses the behavioral and spine defects. We conclude that ErbB2/B4-mediated NRG1 signaling modulates dendritic spine maturation, and that defects at glutamatergic synapses likely contribute to the behavioral abnormalities in ErbB2/B4-deficient mice.

The nature and distribution of the synaptic changes that underlie memory are not well understood. Here we examine the synaptic plasticity behind context fear conditioning in male and female mice and find that new learning produces synaptic potentiation specifically onto engram neurons in the basolateral amygdala. This potentiation lasts at least 7 days, is reversed by extinction, and its disruption impairs memory recall. High frequency optogenetic stimulation of the CS and US-activated ensembles, or biochemical induction of synaptic potentiation in US-responsive neurons alone, is sufficient to produce a context fear association without prior associative training. These results suggest that plasticity of CS inputs onto US-responsive amygdala neurons underlies memory formation and is necessary and sufficient to establish context fear associations.

The use of molecular tools to study the neurobiology of complex behaviors has been hampered by an inability to target the desired changes to relevant groups of neurons. Specific memories and specific sensory representations are sparsely encoded by a small fraction of neurons embedded in a sea of morphologically and functionally similar cells. In this review we discuss genetics techniques that are being developed to address this difficulty. In several studies the use of promoter elements that are responsive to neural activity have been used to drive long-lasting genetic alterations into neural ensembles that are activated by natural environmental stimuli. This approach has been used to examine neural activity patterns during learning and retrieval of a memory, to examine the regulation of receptor trafficking following learning and to functionally manipulate a specific memory trace. We suggest that these techniques will provide a general approach to experimentally investigate the link between patterns of environmentally activated neural firing and cognitive processes such as perception and memory.