Stephen L. Cowen

Phase Precession in Hippocampal Interneurons Showing Strong Functional Coupling to Individual Pyramidal Cells

Although hippocampal interneurons typically do not show discrete regions of elevated firing in an environment, such as seen in pyramidal cell place fields, they do exhibit significant spatial modulation (McNaughton et al., 1983a). Strong monosynaptic coupling between pyramidal neurons and nearby interneurons in the CA1 stratum pyramidale has been strongly implicated on the basis of significant, short-latency peaks in cross-correlogram plots (Csicsvari et al., 1998). Furthermore, interneurons receiving a putative monosynaptic connection from a simultaneously recorded pyramidal cell appear to inherit the spatial modulation of the latter (Marshall et al., 2002). Buzsaki and colleagues hypothesize that interneurons may also adopt the firing phase dynamics of their afferent place cells, which show a phase shift relative to the hippocampal theta rhythm as a rat passes through the place field (“phase precession”). This study confirms and extends the previous reports by showing that interneurons in the dorsal and middle hippocampus with putative monosynaptic connections with place cells recorded on the same tetrode share other properties with their pyramidal cell afferents, including the spatial scale of the place field of pyramidal cell, a characteristic of the septotemporal level of the hippocampus from which the cells are recorded, and the rate of phase precession, which is slower in middle regions. Furthermore, variations in pyramidal cell place field scale within each septotemporal level attributable to task variations are similarly associated with variations in interneuron place field scale. The available data strongly suggest that spatial selectivity of CA1 stratum pyramidale interneurons is inherited from a small cluster of local pyramidal cells and is not a consequence of spatially selective synaptic input from CA3 or other sources.

Anterior cingulate neurons in the rat map anticipated effort and reward to their associated action sequences

Goal-directed behaviors require the consideration and expenditure of physical effort. The anterior cingulate cortex (ACC) appears to play an important role in evaluating effort and reward and in organizing goal-directed actions. Despite agreement regarding the involvement of the ACC in these processes, the way in which effort-, reward-, and motor-related information is registered by networks of ACC neurons is poorly understood. To contrast ACC responses to effort, reward, and motor behaviors, we trained rats on a reversal task in which the selected paths on a track determined the level of effort or reward. Effort was presented in the form of an obstacle that was climbed to obtain reward. We used single-unit recordings to identify neural correlates of effort- and reward-guided behaviors. During periods of outcome anticipation, 52% of recorded ACC neurons responded to the specific route taken to the reward while 21% responded prospectively to effort and 12% responded prospectively to reward. In addition, effort- and reward-selective neurons typically responded to the route, suggesting that these cells integrated motor-related activity with expectations of future outcomes. Furthermore, the activity of ACC neurons did not discriminate between choice and forced trials or respond to a more generalized measure of outcome value. Nearly all neural responses to effort and reward occurred after path selection and were restricted to discrete temporal/spatial stages of the task. Together, these findings support a role for the ACC in integrating route-specific actions, effort, and reward in the service of sustaining discrete movements through an effortful series of goal-directed actions.

2005 Special issue: Firing rate modulation: A simple statistical view of memory trace reactivation

Memory trace reactivation in hippocampal ensembles during sleep has been suggested as a coordinating mechanism for consolidation of new memories. Here we propose a simple statistical scheme allowing analysis of the reactivation of firing rate modulations, with a well-defined null hypothesis. This method allowed reliable detection of ensemble reactivation across three experimental settings. Reactivation of firing rate modulations mirrors several properties of commonly studied reactivation measures: it is stronger during hippocampal sharp waves, and decays over a period of 10-20 min. Moreover, in some conditions, firing rate reactivation covaries with reactivation of cell pair cross-correlations, suggesting the two phenomena reflect similar processes. We propose an attractor network model, with pre-wired attractors, in which experience selects and primes some attractors. Priming occurs by either experience dependent synaptic plasticity or changes in neuronal excitability. Primed attractors are more likely to activate in the following sleep, inducing reactivation of both rates and cross-correlations.

Age Is Associated with Reduced Sharp-Wave Ripple Frequency and Altered Patterns of Neuronal Variability.

Spatial and episodic memory performance declines with age, and the neural basis for this decline is not well understood. Sharp-wave ripples are brief (∼70 ms) high-frequency oscillatory events generated in the hippocampus and are associated with the consolidation of spatial memories. Given the connection between ripple oscillations and memory consolidation, we investigated whether the structure of ripple oscillations and ripple-triggered patterns of single-unit activity are altered in aged rats. Local field and single-unit activity surrounding sharp-wave ripple events were examined in the CA1 region of the hippocampus of old (n = 5) and young (n = 6) F344 rats during periods of rest preceding and following performance on a place-dependent eyeblink-conditioning task. Neural responses in aged rats differed from responses in young rats in several ways. First, compared with young rats, the rate of ripple occurrence (ripple density) is reduced in aged rats during postbehavior rest. Second, mean ripple frequency during prebehavior and postbehavior rest is lower in aged animals (aged: 132 Hz; young: 146 Hz). Third, single neurons in aged animals responded more consistently from ripple to ripple. Fourth, variability in interspike intervals was greater in aged rats. Finally, neurons were tuned to a narrower range of phases of the ripple oscillation relative to young animals. Together, these results suggest that the CA1 network in aged animals has a reduced “vocabulary” of available representational states. SIGNIFICANCE STATEMENT The hippocampus is a structure that is critical for the formation of episodic memories. Sharp-wave ripple events generated in the hippocampus have been implicated in memory consolidation processes critical to memory stabilization. We examine here whether these ripple oscillations are altered over the course of the life span, which could contribute to hippocampus-dependent memory deficits that occur during aging. This experiment used young and aged memory-impaired rats to examine age-related changes in ripple architecture, ripple-triggered spike variance, and spike-phase coherence. We found that there are, indeed, significant changes in characteristics of ripples in older animals that could impact consolidation processes and memory stabilization in the aged brain.

Hedonic and motivational responses to food reward are unchanged in rats with neuropathic pain.

Abstract Rewards influence responses to acute painful stimuli, but the relationship of chronic pain to hedonic or motivational aspects of reward is not well understood. We independently evaluated hedonic qualities of sweet or bitter tastants and motivation to seek food reward in rats with experimental neuropathic pain induced by L5/6 spinal nerve ligation. Hedonic response was measured by implantation of intraoral catheters to allow passive delivery of liquid solutions, and “liking/disliking” responses were scored according to a facial reactivity scale. Spinal nerve ligation rats did not differ from controls in either “liking” or “disliking” reactions to intraoral sucrose or quinine, respectively, at postsurgery day 21, suggesting no differences in perceived hedonic value of sweet or bitter tastants. To assess possible motivational deficits during acute and chronic pain, we used fixed- and progressive-ratio response paradigms of sucrose pellet presentation in rats with transient inflammatory or chronic neuropathic pain. Assessment of response acquisition and break points under the progressive ratio schedule revealed no differences between sham and spinal nerve ligation rats for up to 120 days after injury. However, rats with inflammation showed decrements in lever pressing and break points on days 1 and 2 after complete Freund adjuvant injection that normalized by day 4, consistent with transient ongoing pain. Thus, although acute ongoing inflammatory pain may transiently reduce reward motivation, we did not detect influences of chronic neuropathic pain on hedonic or motivational responses to food rewards. Adaptations that allow normal reward responding to food regardless of chronic pain may be of evolutionary benefit to promote survival.

Repeating firing fields of CA1 neurons shift forward in response to increasing angular velocity

Self-motion information influences spatially-specific firing patterns exhibited by hippocampal neurons. Moreover, these firing patterns can repeat across similar subsegments of an environment, provided that there is similarity of path shape and head orientations across subsegments. The influence of self-motion variables on repeating fields remains to be determined. To investigate the role of path shape and angular rotation on hippocampal activity, we recorded the activity of CA1 neurons from rats trained to run on spiral-shaped tracks. During inbound traversals of circular-spiral tracks, angular velocity increases continuously. Under this condition, most neurons (74%) exhibited repeating fields across at least three adjacent loops. Of these neurons, 86% exhibited forward shifts in the angles of field centers relative to centers on preceding loops. Shifts were absent on squared-spiral tracks, minimal and less reliable on concentric-circle tracks, and absent on outward-bound runs on circular-spiral tracks. However, outward-bound runs on the circular-spiral track in the dark were associated with backward shifts. Together, the most parsimonious interpretation of the results is that continuous increases or decreases in angular velocity are particularly effective at shifting the center of mass of repeating fields, although it is also possible that a nonlinear integration of step counts contributes to the shift. Furthermore, the unexpected absence of field shifts during outward journeys in light (but not darkness) suggests visual cues around the goal location anchored the map of space to an allocentric reference frame.

Intersection of effort and risk: ethological and neurobiological perspectives

The physical effort required to seek out and extract a resource is an important consideration for a foraging animal. A second consideration is the variability or risk associated with resource delivery. An intriguing observation from ethological studies is that animals shift their preference from stable to variable food sources under conditions of increased physical effort or falling energetic reserves. Although theoretical models for this effect exist, no exploration into its biological basis has been pursued. Recent advances in understanding the neural basis of effort- and risk-guided decision making suggest that opportunities exist for determining how effort influences risk preference. In this review, we describe the intersection between the neural systems involved in effort- and risk-guided decision making and outline two mechanisms by which effort-induced changes in dopamine release may increase the preference for variable rewards.

Platform to Enable Combined Measurement of Dopamine and Neural Activity

Complex behaviors depend on the coordination of the activities of ensembles of neurons and the release of neuromodulators such as dopamine. The mechanisms underlying such coordination are not well-understood due to a lack of instrumentation for combined and real-time monitoring of neuromodulator release and the activities of large ensembles of neurons. Here we describe a measurement platform that allows for the combined monitoring of electrophysiology from a high-density electrode array and dopamine dynamics from a carbon-fiber microelectrode. Integration of these two measurement systems was achieved through modification of the existing instrumentation. A shared grounded reference electrode was used in both systems to minimize electrical interference. Further, an optional solid-state-relay array positioned between the electrophysiological electrode array and amplifiers was added to provide additional electrical isolation. The capacity of the integrated measurement platform, termed DANA (Dopamine And Neural Activity), to measure action potentials (high frequency) and local-field oscillations (low frequency) was characterized in vitro using an artificial cerebral spinal fluid gelatin. In vivo recordings from the DANA platform in anesthetized rats demonstrated the ability of the system for near-simultaneous measurement of dopamine release and activity from multiple neurons both in distant brain regions (striatum and hippocampus) and within the same brain region (striatum). Furthermore, this system was shown to be sufficiently compact to measure activity in freely moving animals through recording of single-neuron activity, high-frequency local-field oscillations, and dopamine release.

Chronic pain impairs cognitive flexibility and engages novel learning strategies in rats

Abstract Cognitive flexibility, the ability to adapt behavior to changing outcomes, is critical to survival. The prefrontal cortex is a key site of cognitive control, and chronic pain is known to lead to significant morphological changes to this brain region. Nevertheless, the effects of chronic pain on cognitive flexibility and learning remain uncertain. We used an instrumental paradigm to assess adaptive learning in an experimental model of chronic pain induced by tight ligation of the spinal nerves L5/6 (spinal nerve ligation model). Naive, sham-operated, and spinal nerve ligation (SNL) rats were trained to perform fixed-ratio, variable-ratio, and contingency-shift behaviors for food reward. Although all groups learned an initial lever-reward contingency, learning was slower in SNL animals in a subsequent choice task that reversed reinforcement contingencies. Temporal analysis of lever-press responses across sessions indicated no apparent deficits in memory consolidation or retrieval. However, analysis of learning within sessions revealed that the lever presses of SNL animals occurred in bursts, followed by delays. Unexpectedly, the degree of bursting correlated positively with learning. Under a variable-ratio probabilistic task, SNL rats chose a less profitable behavioral strategy compared with naive and sham-operated animals. After extinction of behavior for learned preferences, SNL animals reverted to their initially preferred (ie, less profitable) behavioral choice. Our data suggest that in the face of uncertainty, chronic pain drives a preference for familiar associations, consistent with reduced cognitive flexibility. The observed burst-like responding may represent a novel learning strategy in animals with chronic pain.

Crossing borders: sleep reactivation as a window on cell assembly formation

Learning is believed to be a result of plasticity in synaptic architecture, but few studies have shown this directly. A new paper explores a mechanism that shapes the formation of associative connections between neurons in behaving animals.