Pattern completion, the ability to retrieve complete memories on the basis of incomplete sets of cues, is a crucial function of biological memory systems. The extensive recurrent connectivity of the CA3 area of hippocampus has led to suggestions that it might provide this function. We have tested this hypothesis by generating and analyzing a genetically engineered mouse strain in which the N-methyl-D-asparate (NMDA) receptor gene is ablated specifically in the CA3 pyramidal cells of adult mice. The mutant mice normally acquired and retrieved spatial reference memory in the Morris water maze, but they were impaired in retrieving this memory when presented with a fraction of the original cues. Similarly, hippocampal CA1 pyramidal cells in mutant mice displayed normal place-related activity in a full-cue environment but showed a reduction in activity upon partial cue removal. These results provide direct evidence for CA3 NMDA receptor involvement in associative memory recall.

Subcellular-sized, ultraflexible electrodes form seamless integration with the living brain and afford chronically reliable recording.

Hippocampal long-term potentiation (LTP) induced by theta-burst pairing of Schaffer collateral inputs and postsynaptic firing is associated with localized increases in synaptic strength and dendritic excitability. Using the same protocol, we now demonstrate a decrease in cellular excitability that was blocked by the h-channel blocker ZD7288. This decrease was also induced by postsynaptic theta-burst firing alone, yet it was blocked by NMDA receptor antagonists, postsynaptic Ca2+ chelation, low concentrations of tetrodotoxin, omega-conotoxin MVIIC, calcium/calmodulin-dependent protein kinase II (CaMKII) inhibitors and a protein synthesis inhibitor. Increasing network activity with high extracellular K+ caused a similar reduction of cellular excitability and an increase in h-channel HCN1 protein. We propose that backpropagating action potentials open glutamate-bound NMDA receptors, resulting in an increase in I(h) and a decrease in overall excitability. The occurrence of such a reduction in cellular excitability in parallel with synaptic potentiation would be a negative feedback mechanism to normalize neuronal output firing and thus promote network stability.

Mnemonic persistent activity in the prefrontal cortex (PFC) constitutes the neural basis of working memory. To understand how neuromodulators contribute to the generation of persistent activity, it is necessary to identify the intrinsic properties of the layer V pyramidal neurons that transfer this information to downstream networks. Here we show that the somatic dynamic and integrative properties of layer V pyramidal neurons in the rat medial PFC depend on whether they project subcortically to the pons [corticopontine (CPn)] or to the contralateral cortex [commissural (COM)]. CPn neurons display low temporal summation and accelerate in firing frequency when depolarized, whereas COM neurons have high temporal summation and display spike frequency accommodation. In response to dynamic stimuli, COM neurons act as low-pass filters, whereas CPn neurons act as bandpass filters, resonating in the theta frequency range (3-6 Hz). The disparate subthreshold properties of COM and CPn neurons can be accounted for by differences in the hyperpolarizationactivated cyclic nucleotide gated cation h-current. Interestingly, neuromodulators hypothesized to enhance mnemonic persistent activity affect COM and CPn neurons distinctly. Adrenergic modulation shifts the dynamic properties of CPn but not COM neurons and increases the excitability of CPn neurons significantly more than COM neurons. In response to cholinergic modulation, CPn neurons were much more likely to display activity-dependent intrinsic persistent firing than COM neurons. Together, these data suggest that the two categories of projection neurons may subserve separate functions in PFC and may be engaged differently during working memory processes.

Siegel JJ, Kalmbach B, Chitwood RA, Mauk MD. Persistent activity in a cortical-to-subcortical circuit: bridging the temporal gap in trace eyelid conditioning. J Neurophysiol 107: 50-64, 2012. First published September 28, 2011 doi:10.1152/jn.00689.2011We have addressed the source and nature of the persistent neural activity that bridges the stimulusfree gap between the conditioned stimulus (CS) and unconditioned stimulus (US) during trace eyelid conditioning. Previous work has demonstrated that this persistent activity is necessary for trace eyelid conditioning: CS-elicited activity in mossy fiber inputs to the cerebellum does not extend into the stimulus-free trace interval, which precludes the cerebellar learning that mediates conditioned response expression. In behaving rabbits we used in vivo recordings from a region of medial prefrontal cortex (mPFC) that is necessary for trace eyelid conditioning to test the hypothesis that neurons there generate activity that persists beyond CS offset. These recordings revealed two patterns of activity during the trace interval that would enable cerebellar learning. Activity in some cells began during the tone CS and persisted to overlap with the US, whereas in other cells, activity began during the stimulus-free trace interval. Injection of anterograde tracers into this same region of mPFC revealed dense labeling in the pontine nuclei, where recordings also revealed tone-evoked persistent activity during trace conditioning. These data suggest a corticopontine pathway that provides an input to the cerebellum during trace conditioning trials that bridges the temporal gap between the CS and US to engage cerebellar learning. As such, trace eyelid conditioning represents a well-characterized and experimentally tractable system that can facilitate mechanistic analyses of cortical persistent activity and how it is used by downstream brain structures to influence behavior. single units; medial prefrontal cortex; classical conditioning; pontine nuclei; dextran tracer THE ABILITY TO USE PRIOR ASSOCIATIVE learning to predict events and guide actions is essential to survival. Because events are often separated in time, the neural mechanisms of forming associations between events that do not overlap in time are of particular interest. Several forebrain regions appear to be specialized for this purpose, because they contain neurons capable of generating activity that persists beyond the termination of one stimulus to overlap in time with an associated second stimulus. These persistent responses, such as those observed in primate prefrontal cortex during delayed-response tasks, are hypothesized to contribute to working memory and other cognitive processes by maintaining spike activity between a cue and the later reinforcement that it predicts (Curtis 2006; Frank and Brown 2003;Fuster 2001;Goldman-Rakic 1995). These findings highlight the need to understand how cortical persistent activity is used by downstream brain regions to influence behavior.

Routh BN, Johnston D, Harris K, Chitwood RA. Anatomical and electrophysiological comparison of CA1 pyramidal neurons of the rat and mouse. J Neurophysiol 102: 2288 -2302, 2009. First published August 12, 2009 doi:10.1152/jn.00082.2009. The study of learning and memory at the single-neuron level has relied on the use of many animal models, most notably rodents. Although many physiological and anatomical studies have been carried out in rats, the advent of genetically engineered mice has necessitated the comparison of new results in mice to established results from rats. Here we compare fundamental physiological and morphological properties and create three-dimensional compartmental models of identified hippocampal CA1 pyramidal neurons of one strain of rat, SpragueDawley, and two strains of mice, C57BL/6 and 129/SvEv. We report several differences in neuronal physiology and anatomy among the three animal groups, the most notable being that neurons of the 129/SvEv mice, but not the C57BL/6 mice, have higher input resistance, lower dendritic surface area, and smaller spines than those of rats. A surprising species-specific difference in membrane resonance indicates that both mouse strains have lower levels of the hyperpolarization-activated nonspecific cation current I h . Simulations suggest that differences in I h kinetics rather than maximal conductance account for the lower resonance. Our findings indicate that comparisons of data obtained across strains or species will need to account for these and potentially other physiological and anatomical differences.

1. Serotonin (5-HT) facilitates the connections between sensory and motor neurons in Aplysia during behavioural sensitization. The effect of 5-HT on sensorimotor synapses is believed to be primarily presynaptic. Here we tested whether 5-HT can have an exclusively postsynaptic facilitatory effect.2. Siphon motor neurons were individually dissociated from the abdominal ganglion of Aplysia and placed into cell culture. Brief pulses of glutamate, the putative sensory neuron transmitter, were focally applied (0.1 Hz) to solitary motor neurons in culture, and the glutamate-evoked postsynaptic potentials (Glu-PSPs) were recorded.3. When 5-HT was perfused over the motor neuron for 10 min, the amplitude of the Glu-PSPs was significantly increased. The 5-HT-induced enhancement of the Glu-PSPs persisted for at least 40 min after washout.4. Prior injection into the motor neuron of the calcium chelator BAPTA, GDP-b-S or GTP-y-S blocked the 5-HT-induced facilitation of the Glu-PSPs. However, the facilitation was not blocked when APV, an NMDA receptor antagonist, was applied together with the 5-HT.5. The enhancement of the Glu-PSPs by 5-HT was reversed by the AMPA receptor antagonist DNQX, indicating that 5-HT increased the functional expression of AMPA-type receptors in the motor neuron.6. The presence of botulinum toxin in the motor neuron blocked the 5-HT-induced enhancement of the Glu-PSPs. As botulinum toxin prevents exocytosis we hypothesize that during sensitization 5-HT causes the insertion of additional AMPA-type receptors into the postsynaptic membrane of sensorimotor synapses via exocytosis. This postsynaptic mechanism may contribute to facilitation of the synapses.

The firing of inhibitory interneurones, like all excitable neurones, is contingent upon how synaptic potentials are integrated and how action potentials are triggered. The electrotonic structure of a neurone, determined by its morphology and passive membrane properties, underlies the integration of synaptic signals, as well as voltage-dependent interactions between synapses (Rall, 1962). In turn, the analysis of electrotonic structure forms the framework for studying the active properties of neurones as it shapes the temporal and spatial distribution of potentials that activate non-linear conductances. The detailed examination of neuronal electrotonic structure has been performed for many types of neurones including CA1 pyramidal neurones, CA3 pyramidal neurones, neocortical pyramidal neurones, cerebellar Purkinje cells, motor neurones and CA1 interneurones (Stratford et al. 1989;Major et al. 1994;Rapp et al. 1994;Mainen et al. 1996;Carnevale et al. 1997). The general principles of cable theory, first developed by Rall (1962), are supported in all of these models (e.g. synaptic signals attenuate from the dendrite to the soma).