Recent results suggest that social memory requires the dorsal hippocampal CA2 region as well as a subset of ventral CA1 neurons. However, it is unclear whether dorsal CA2 and ventral CA1 represent parallel or sequential circuits. Moreover, because evidence implicating CA2 in social memory comes largely from long-term inactivation experiments, the dynamic role of CA2 in social memory remains unclear. Here, we use pharmacogenetics and optogenetics in mice to acutely and reversibly silence dorsal CA2 and its projections to ventral hippocampus. We show that dorsal CA2 activity is critical for encoding, consolidation, and recall phases of social memory. Moreover, dorsal CA2 contributes to social memory by providing strong excitatory input to the same subregion of ventral CA1 that contains the subset of neurons implicated in social memory. Thus, our studies provide new insights into a dorsal CA2 to ventral CA1 circuit whose dynamic activity is necessary for social memory.

Upon entry into the central nervous system (CNS), serum insulin-like growth factor-1 (IGF-I) modulates neuronal growth, survival, and excitability. Yet mechanisms that trigger IGF-I entry across the blood-brain barrier remain unclear. We show that neuronal activity elicited by electrical, sensory, or behavioral stimulation increases IGF-I input in activated regions. Entrance of serum IGF-I is triggered by diffusible messengers (i.e., ATP, arachidonic acid derivatives) released during neurovascular coupling. These messengers stimulate matrix metalloproteinase-9, leading to cleavage of the IGF binding protein-3 (IGFBP-3). Cleavage of IGFBP-3 allows the passage of serum IGF-I into the CNS through an interaction with the endothelial transporter lipoprotein related receptor 1. Activity-dependent entrance of serum IGF-I into the CNS may help to explain disparate observations such as proneurogenic effects of epilepsy, rehabilitatory effects of neural stimulation, and modulatory effects of blood flow on brain activity.

Summary Although the hippocampus is known to be important for declarative memory, how hippocampal output regulates motivated behaviors, such as social aggression, is less well understood. Here we report that hippocampal CA2 pyramidal neurons, which are important for social memory, promote social aggression. This action depends on CA2 output to the lateral septum that is selectively enhanced immediately prior to attack. Activation of lateral septum by CA2 recruits a circuit that disinhibits a subnucleus of the ventro-medial hypothalamus known to trigger attack. The social hormone arginine-vasopressin enhances social aggression by acting on arginine-vasopressin 1b receptors on CA2 presynaptic terminals in lateral septum to facilitate excitatory synaptic transmission. In this manner, release of vasopressin in lateral septum, driven by an animal’s internal state, may serve as a modulatory control that determines whether CA2 activity leads to declarative memory of a social encounter or proceeds to promote motivated social aggression.

In amyotrophic lateral sclerosis (ALS) the large motoneurons that innervate the fast-contracting muscle fibers (F-type motoneurons) are vulnerable and degenerate in adulthood. In contrast, the small motoneurons that innervate the slow-contracting fibers (S-type motoneurons) are resistant and do not degenerate. Intrinsic hyperexcitability of F-type motoneurons during early postnatal development has long been hypothesized to contribute to neural degeneration in the adult. Here, we performed a critical test of this hypothesis by recording from identified F- and S-type motoneurons in the superoxide dismutase-1 mutant G93A (mSOD1), a mouse model of ALS at a neonatal age when early pathophysiological changes are observed. Contrary to the standard hypothesis, excitability of F-type motoneurons was unchanged in the mutant mice. Surprisingly, the S-type motoneurons of mSDO1 mice did display intrinsic hyperexcitability (lower rheobase, hyperpolarized spiking threshold). As S-type motoneurons are resistant in ALS, we conclude that early intrinsic hyperexcitability does not contribute to motoneuron degeneration.DOI: http://dx.doi.org/10.7554/eLife.04046.001

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The fast contraction time of mouse motor units creates a unique situation in which motoneurons have to fire at low frequencies to produce small forces but also at very high frequency (much higher than in cat or rat motoneurons) to reach the fusion frequency of their motor units. To understand how this problem is solved, we performed intracellular recordings of adult mouse spinal motoneurons and investigated systematically their subthreshold properties and their discharge pattern. We show that mouse motoneurons have a much wider range of firing frequencies than cat and rat motoneurons because of three salient features. First, they have a short membrane time constant. This results in a higher cutoff frequency and a higher resonance frequency, which allow mouse motoneurons to integrate inputs at higher frequencies. Second, their afterhyperpolarization (AHP) is faster, allowing the motoneurons to discharge at a higher rate. Third, motoneurons display high-frequency (100 -150 Hz) subthreshold oscillations during the interspike intervals. The fast membrane kinetics greatly favors the appearance of these oscillations, creating a "subprimary range" of firing. In this range, which has never been reported in cat and in rat spinal motoneurons, the oscillations follow the AHP and trigger spiking after a variable delay, allowing a discharge at low frequency but at the expense of an irregular rate.

Over the past half-century, we have gained significant insights into the molecular biology of long-term memory storage at the level of the synapse. In recent years, our understanding of the cellular architecture supporting long-term memory traces has also substantially improved. However, the molecular biology of consolidation at the level of neuronal systems has been relatively neglected. In this opinion article, we first examine our current understanding of the cellular mechanisms of synaptic consolidation. We then outline areas requiring further investigation on how cellular changes contribute to systems consolidation. Finally, we highlight recent findings on the cellular architecture of memory traces in rodents and how the application of new technologies will expand our understanding of systems consolidation at the neural circuit level. In the coming years, this research focus will be critical for understanding the evolution of long-term memories and for enabling the development of novel therapeutics which embrace the dynamic nature of memories.

Summary Input-timing dependent plasticity (ITDP) is a circuit-based synaptic learning rule whereby precisely timed, paired activation of direct entorhinal cortex (EC) and Schaffer collateral (SC) inputs to hippocampal CA1 pyramidal neurons (PNs) produces a long-term enhancement of CA1 SC excitation, which has been linked to specificity of contextual memory. We report that paired activation of EC and SC inputs also increases SC excitation of CA2 PNs, which are important for social memory. However, whereas CA1 ITDP depends on endocannabinoid CB1 receptor-dependent long-term depression of feedforward inhibition (iLTD) mediated by cholecystokinin-positive interneurons, CA2 ITDP depends on δ-opioid receptor-dependent iLTD of parvalbumin-positive interneuron inhibition. Blockade of CA2 δ-opioid receptors blocked ITDP and impaired social memory whereas a social encounter with a novel animal decreased CA2 feedforward inhibition and occluded ITDP. Thus, ITDP may provide a more general synaptic learning rule for distinct forms of hippocampal-dependent memory through its recruitment by distinct hippocampal regions.