Blake A. Richards

Hippocampal Neurogenesis Regulates Forgetting During Adulthood and Infancy

Forget It! When examining the relationship between the production of new neurons in the hippocampus and memory, studies have generally first manipulated hippocampal neurogenesis and afterward investigated memory formation and found that new neurons help to encode new memories. However, when investigating how similar manipulations of neurogenesis impact established hippocampus-dependent memories, Akers et al. (p. 598; see the Perspective by Mongiat and Schinder) uncovered a role for neurogenesis in memory clearance. Thus, the continuous addition of new neurons both degrades existing information stored in hippocampal circuits and simultaneously provides substrates for new learning. Addition of new neurons leads to remodeling of hippocampal circuitry and memory degradation. [Also see Perspective by Mongiat and Schinder] Throughout life, new neurons are continuously added to the dentate gyrus. As this continuous addition remodels hippocampal circuits, computational models predict that neurogenesis leads to degradation or forgetting of established memories. Consistent with this, increasing neurogenesis after the formation of a memory was sufficient to induce forgetting in adult mice. By contrast, during infancy, when hippocampal neurogenesis levels are high and freshly generated memories tend to be rapidly forgotten (infantile amnesia), decreasing neurogenesis after memory formation mitigated forgetting. In precocial species, including guinea pigs and degus, most granule cells are generated prenatally. Consistent with reduced levels of postnatal hippocampal neurogenesis, infant guinea pigs and degus did not exhibit forgetting. However, increasing neurogenesis after memory formation induced infantile amnesia in these species.

Neurons Are Recruited to a Memory Trace Based on Relative Neuronal Excitability Immediately before Training

Memories are thought to be sparsely encoded in neuronal networks, but little is known about why a given neuron is recruited or allocated to a particular memory trace. Previous research shows that in the lateral amygdala (LA), neurons with increased CREB are selectively recruited to a fear memory trace. CREB is a ubiquitous transcription factor implicated in many cellular processes. Which process mediates neuronal memory allocation? One hypothesis is that CREB increases neuronal excitability to bias neuronal recruitment, although this has not been shown experimentally. Here we use several methods to increase neuronal excitability and show this both biases recruitment into the memory trace and enhances memory formation. Moreover, artificial activation of these neurons alone is a sufficient retrieval cue for fear memory expression, showing that these neurons are critical components of the memory trace. These results indicate that neuronal memory allocation is based on relative neuronal excitability immediately before training.

Patterns across multiple memories are identified over time

Memories are not static but continue to be processed after encoding. This is thought to allow the integration of related episodes via the identification of patterns. Although this idea lies at the heart of contemporary theories of systems consolidation, it has yet to be demonstrated experimentally. Using a modified water-maze paradigm in which platforms are drawn stochastically from a spatial distribution, we found that mice were better at matching platform distributions 30 d compared to 1 d after training. Post-training time-dependent improvements in pattern matching were associated with increased sensitivity to new platforms that conflicted with the pattern. Increased sensitivity to pattern conflict was reduced by pharmacogenetic inhibition of the medial prefrontal cortex (mPFC). These results indicate that pattern identification occurs over time, which can lead to conflicts between new information and existing knowledge that must be resolved, in part, by computations carried out in the mPFC.

A double dissociation of dorsal and ventral hippocampal function on a learning and memory task mediated by the dorso‐lateral striatum

The objectives of this research were to further delineate the neural circuits subserving proposed memory‐based behavioural subsystems in the hippocampal formation. These studies were guided by anatomical evidence showing a topographical organization of the hippocampal formation. Briefly, perpendicular to the medial/lateral entorhinal cortex division there is a second system of parallel circuits that separates the dorsal and ventral hippocampus. Recent work from this laboratory has provided evidence that the hippocampus incidentally encodes a context‐specific inhibitory association during acquisition of a visual discrimination task. One question that emerges from this dataset is whether the dorsal or ventral hippocampus makes a unique contribution to this newly described function. Rats with neurotoxic lesions of the dorsal or ventral hippocampus were assessed on the acquisition of the visual discrimination task. Following asymptotic performance they were given reversal training in either the same or a different context from the original training. The results showed that the context‐specific inhibition effect is mediated by a circuit that includes the ventral but not the dorsal hippocampus. Results from a control procedure showed that rats with either dorso‐lateral striatum damage or dorsal hippocampal lesions were impaired on a tactile/spatial discrimination. Taken together, the results represent a double dissociation of learning and memory function between the ventral and dorsal hippocampus. The formation of an incidental inhibitory association was dependent on ventral but not dorsal hippocampal circuitry, and the opposite dependence was found for the spatial component of a tactile/spatial discrimination.

The Persistence and Transience of Memory

The predominant focus in the neurobiological study of memory has been on remembering (persistence). However, recent studies have considered the neurobiology of forgetting (transience). Here we draw parallels between neurobiological and computational mechanisms underlying transience. We propose that it is the interaction between persistence and transience that allows for intelligent decision-making in dynamic, noisy environments. Specifically, we argue that transience (1) enhances flexibility, by reducing the influence of outdated information on memory-guided decision-making, and (2) prevents overfitting to specific past events, thereby promoting generalization. According to this view, the goal of memory is not the transmission of information through time, per se. Rather, the goal of memory is to optimize decision-making. As such, transience is as important as persistence in mnemonic systems.

Towards deep learning with segregated dendrites

Deep learning has led to significant advances in artificial intelligence, in part, by adopting strategies motivated by neurophysiology. However, it is unclear whether deep learning could occur in the real brain. Here, we show that a deep learning algorithm that utilizes multi-compartment neurons might help us to understand how the neocortex optimizes cost functions. Like neocortical pyramidal neurons, neurons in our model receive sensory information and higher-order feedback in electrotonically segregated compartments. Thanks to this segregation, neurons in different layers of the network can coordinate synaptic weight updates. As a result, the network learns to categorize images better than a single layer network. Furthermore, we show that our algorithm takes advantage of multilayer architectures to identify useful higher-order representations—the hallmark of deep learning. This work demonstrates that deep learning can be achieved using segregated dendritic compartments, which may help to explain the morphology of neocortical pyramidal neurons.

Bidirectional Control of Anxiety-Related Behaviors in Mice: Role of Inputs Arising from the Ventral Hippocampus to the Lateral Septum and Medial Prefrontal Cortex

Anxiety is an adaptive response to potentially threatening situations. Exaggerated and uncontrolled anxiety responses become maladaptive and lead to anxiety disorders. Anxiety is shaped by a network of forebrain structures, including the hippocampus, septum, and prefrontal cortex. In particular, neural inputs arising from the ventral hippocampus (vHPC) to the lateral septum (LS) and medial prefrontal cortex (mPFC) are thought to serve as principal components of the anxiety circuit. However, the role of vHPC-to-LS and vHPC-to-mPFC signals in anxiety is unclear, as no study has directly compared their behavioral contribution at circuit level. We targeted LS-projecting vHPC cells and mPFC-projecting vHPC cells by injecting the retrogradely propagating canine adenovirus encoding Cre recombinase into the LS or mPFC, and injecting a Cre-responsive AAV (AAV8-hSyn-FLEX-hM3D or hM4D) into the vHPC. Consequences of manipulating these neurons were examined in well-established tests of anxiety. Chemogenetic manipulation of LS-projecting vHPC cells led to bidirectional changes in anxiety: activation of LS-projecting vHPC cells decreased anxiety whereas inhibition of these cells produced opposite anxiety-promoting effects. The observed anxiety-reducing function of LS-projecting cells was in contrast with the function of mPFC-projecting cells, which promoted anxiety. In addition, double retrograde tracing demonstrated that LS- and mPFC-projecting cells represent two largely anatomically distinct cell groups. Altogether, our findings suggest that the vHPC houses discrete populations of cells that either promote or suppress anxiety through differences in their projection targets. Disruption of the intricate balance in the activity of these two neuron populations may drive inappropriate behavioral responses seen in anxiety disorders.

The conjunctive trace.

Memories serve to establish some permanence to our inner lives despite the fleeting nature of subjective experience. Most neurobiological theories of memory assume that this mental permanence reflects an underlying cellular permanence. Namely, it is assumed that the cellular changes which first occur to store a memory are perpetuated for as long as the memory is stored. But is that really the case? In an opinion piece in this issue of Hippocampus, Aryeh Routtenberg raises the provocative idea that the subjective sense of memory persistence is not in fact a result of persistence at the cellular level, rather, that “supple synapses” and multiple “evanescent networks” that are forever changing are responsible for our memories. On one level, his proposal could be construed as a radical challenge to some of our most fundamental theories of the neurobiology of memory, including Donald Hebbs proposal that memories are stored by networks that strengthen their connections to increase the likelihood of the same activity patterns being recreated at a later date. However, it could also be seen as a moderating call, a call for a greater acknowledgement of the dynamic, stochastic, and distributed nature of neural networks. In this response to Routtenbergs article, we attempt to provide a clarification of the dividing line between these two interpretations of his argument, and in doing so, we provide some overview of the empirical evidence that bears on this subject. We argue that the data that exists to date favors the more moderate interpretation: that memory storage involves a process in which activity patterns are made more likely to reoccur, but that an under‐appreciated reality is that mnemonic traces may continue to change and evolve over time.

Parvalbumin-positive interneurons mediate neocortical-hippocampal interactions that are necessary for memory consolidation

Following learning, increased coupling between spindle oscillations in the medial prefrontal cortex (mPFC) and ripple oscillations in the hippocampus is thought to underlie memory consolidation. However, whether learning-induced increases in ripple-spindle coupling are necessary for successful memory consolidation has not been tested directly. In order to decouple ripple-spindle oscillations, here we chemogenetically inhibited parvalbumin-positive (PV+) interneurons, since their activity is important for regulating the timing of spiking activity during oscillations. We found that contextual fear conditioning increased ripple-spindle coupling in mice. However, inhibition of PV+ cells in either CA1 or mPFC eliminated this learning-induced increase in ripple-spindle coupling without affecting ripple or spindle incidence. Consistent with the hypothesized importance of ripple-spindle coupling in memory consolidation, post-training inhibition of PV+ cells disrupted contextual fear memory consolidation. These results indicate that successful memory consolidation requires coherent hippocampal-neocortical communication mediated by PV+ cells.

Neuronal chloride and excitability — the big impact of small changes

Synaptic inhibition is a critical regulator of neuronal excitability, and in the mature brain the majority of synaptic inhibition is mediated by Cl--permeable GABAA receptors. Unlike other physiologically relevant ions, Cl- is dynamically regulated, and alterations in the Cl- gradient can have significant impact on neuronal excitability. Due to changes in the neuronal Cl- concentration, GABAergic transmission can bidirectionally regulate the induction of excitatory synaptic plasticity and gate the closing of the critical period for monocular deprivation in visual cortex. GABAergic circuitry can also provide a powerful restraining mechanism for the spread of excitation, however Cl- extrusion mechanisms can become overwhelmed and GABA can paradoxically contribute to pathological excitation such as the propagation of seizure activity.