Laura Lee Colgin

Frequency of gamma oscillations routes flow of information in the hippocampus

Gamma oscillations are thought to transiently link distributed cell assemblies that are processing related information, a function that is probably important for network processes such as perception, attentional selection and memory. This ‘binding’ mechanism requires that spatially distributed cells fire together with millisecond range precision; however, it is not clear how such coordinated timing is achieved given that the frequency of gamma oscillations varies substantially across space and time, from ∼25 to almost 150 Hz. Here we show that gamma oscillations in the CA1 area of the hippocampus split into distinct fast and slow frequency components that differentially couple CA1 to inputs from the medial entorhinal cortex, an area that provides information about the animal’s current position, and CA3, a hippocampal subfield essential for storage of such information. Fast gamma oscillations in CA1 were synchronized with fast gamma in medial entorhinal cortex, and slow gamma oscillations in CA1 were coherent with slow gamma in CA3. Significant proportions of cells in medial entorhinal cortex and CA3 were phase-locked to fast and slow CA1 gamma waves, respectively. The two types of gamma occurred at different phases of the CA1 theta rhythm and mostly on different theta cycles. These results point to routeing of information as a possible function of gamma frequency variations in the brain and provide a mechanism for temporal segregation of potentially interfering information from different sources.

Cross-frequency coupling between neuronal oscillations

Electrophysiological recordings in animals, including humans, are modulated by oscillatory activities in several frequency bands. Little is known about how oscillations in various frequency bands interact. Recent findings from the human neocortex show that the power of fast gamma oscillations (30-150Hz) is modulated by the phase of slower theta oscillations (5-8Hz). Given that this coupling reflects a specific interplay between large ensembles of neurons, it is likely to have profound implications for neuronal processing.

Mechanisms of Late-Onset Cognitive Decline after Early-Life Stress

Progressive cognitive deficits that emerge with aging are a result of complex interactions of genetic and environmental factors. Whereas much has been learned about the genetic underpinnings of these disorders, the nature of “acquired” contributing factors, and the mechanisms by which they promote progressive learning and memory dysfunction, remain largely unknown. Here, we demonstrate that a period of early-life “psychological” stress causes late-onset, selective deterioration of both complex behavior and synaptic plasticity: two forms of memory involving the hippocampus, were severely but selectively impaired in middle-aged, but not young adult, rats exposed to fragmented maternal care during the early postnatal period. At the cellular level, disturbances to hippocampal long-term potentiation paralleled the behavioral changes and were accompanied by dendritic atrophy and mossy fiber expansion. These findings constitute the first evidence that a short period of stress early in life can lead to delayed, progressive impairments of synaptic and behavioral measures of hippocampal function, with potential implications to the basis of age-related cognitive disorders in humans.

Understanding memory through hippocampal remapping

Memory interference is a common cause of forgetting. Interference is a byproduct of the need to balance the formation of well-differentiated representations against the ability to retrieve memories from cues that are not identical to the original experience. How the brain accomplishes this has remained elusive. Here we review how insights can be gained from studies of an apparently unrelated phenomenon in the rodent brain--remapping in hippocampal place cells. Remapping refers to the formation of distinct representations in populations of place cells after minor changes in inputs to the hippocampus. Remapping might reflect processes involved generally in decorrelation of overlapping signals. These processes might be crucial for storing large numbers of similar experiences with only minimal interference.

Coordination of entorhinal-hippocampal ensemble activity during associative learning

Accumulating evidence points to cortical oscillations as a mechanism for mediating interactions among functionally specialized neurons in distributed brain circuits. A brain function that may use such interactions is declarative memory—that is, memory that can be consciously recalled, such as episodes and facts. Declarative memory is enabled by circuits in the entorhinal cortex that interface the hippocampus with the neocortex. During encoding and retrieval of declarative memories, entorhinal and hippocampal circuits are thought to interact via theta and gamma oscillations, which in awake rodents predominate frequency spectra in both regions. In favour of this idea, theta–gamma coupling has been observed between entorhinal cortex and hippocampus under steady-state conditions in well-trained rats; however, the relationship between interregional coupling and memory formation remains poorly understood. Here we show, by multisite recording at successive stages of associative learning, that the coherence of firing patterns in directly connected entorhinal–hippocampus circuits evolves as rats learn to use an odour cue to guide navigational behaviour, and that such coherence is invariably linked to the development of ensemble representations for unique trial outcomes in each area. Entorhinal–hippocampal coupling was observed specifically in the 20–40-hertz frequency band and specifically between the distal part of hippocampal area CA1 and the lateral part of entorhinal cortex, the subfields that receive the predominant olfactory input to the hippocampal region. Collectively, the results identify 20–40-hertz oscillations as a mechanism for synchronizing evolving representations in dispersed neural circuits during encoding and retrieval of olfactory–spatial associative memory.

Gamma Oscillations in the Hippocampus

Gamma oscillations are thought to temporally link the activity of distributed cells. We discuss mechanisms of gamma oscillations in the hippocampus and review evidence supporting a functional role for such oscillations in several key hippocampal operations, including cell grouping, dynamic routing, and memory. We propose that memory encoding and retrieval are coordinated by different frequencies of hippocampal gamma oscillations and suggest how transitions between slow and fast gamma may occur.

Spatial Representation along the Proximodistal Axis of CA1

CA1 cells receive direct input from space-responsive cells in medial entorhinal cortex (MEC), such as grid cells, as well as more nonspatial cells in lateral entorhinal cortex (LEC). Because MEC projects preferentially to the proximal part of the CA1, bordering CA2, whereas LEC innervates only the distal part, bordering subiculum, we asked if spatial tuning is graded along the transverse axis of CA1. Tetrodes were implanted along the entire proximodistal axis of dorsal CA1 in rats. Data were recorded in cylinders large enough to elicit firing at more than one location in many neurons. Distal CA1 cells showed more dispersed firing and had a larger number of firing fields than proximal cells. Phase-locking of spikes to MEC theta oscillations was weaker in distal CA1 than in proximal CA1. The findings suggest that spatial firing in CA1 is organized transversally, with the strongest spatial modulation occurring in the MEC-associated proximal part.

Oscillations and hippocampal-prefrontal synchrony.

The hippocampus, a structure required for many types of memory, connects to the medial prefrontal cortex, an area that helps direct neuronal information streams during intentional behaviors. Increasing evidence suggests that oscillations regulate communication between these two regions. Theta rhythms may facilitate hippocampal inputs to the medial prefrontal cortex during mnemonic tasks and may also integrate series of functionally relevant gamma-mediated cell assemblies in the medial prefrontal cortex. During slow-wave sleep, temporal coordination of hippocampal sharp wave-ripples and medial prefrontal cortex spindles may be an important component of the process by which memories become hippocampus-independent. Studies using rodent models indicate that oscillatory phase-locking is disturbed in schizophrenia, emphasizing the need for more studies of oscillatory synchrony in the hippocampal-prefrontal network.

Long-term potentiation is impaired in middle-aged rats: regional specificity and reversal by adenosine receptor antagonists.

Memory loss in humans begins early in adult life and progresses thereafter. It is not known whether these losses reflect the failure of cellular processes that encode memory or disturbances in events that retrieve it. Here, we report that impairments in hippocampal long-term potentiation (LTP), a form of synaptic plasticity associated with memory, are present by middle age in rats but only in select portions of pyramidal cell dendritic trees. Specifically, LTP induced with theta-burst stimulation in basal dendrites of hippocampal field CA1 decayed rapidly in slices prepared from 7- to 10-month-old rats but not in slices from young adults. There were no evident age-related differences in LTP in the apical dendrites. Both the adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine and a positive AMPA receptor modulator (ampakine) offset age-related LTP deficits. Adenosine produced greater depression of synaptic responses in middle-aged versus young adult slices and in basal versus apical dendrites. These results were not associated with variations in A1 receptor densities and may instead reflect regional and age-related differences in adenosine clearance. Pertinent to this, brief applications of A1 receptor antagonists immediately after theta stimulation fully restored LTP in middle-aged rats. We hypothesize that the build-up of extracellular adenosine during theta activity persists into the postinduction period in the basal dendrites of middle-aged slices and thereby activates the A1 receptor-dependent LTP reversal effect. Regardless of the underlying mechanism, the present results provide a candidate explanation for memory losses during normal aging and indicate that, with regard to plasticity, different segments of pyramidal neurons age at different rates.

Rhythms of the hippocampal network

The hippocampal local field potential (LFP) shows three major types of rhythms: theta, sharp wave–ripples and gamma. These rhythms are defined by their frequencies, they have behavioural correlates in several species including rats and humans, and they have been proposed to carry out distinct functions in hippocampal memory processing. However, recent findings have challenged traditional views on these behavioural functions. In this Review, I discuss our current understanding of the origins and the mnemonic functions of hippocampal theta, sharp wave–ripples and gamma rhythms on the basis of findings from rodent studies. In addition, I present an updated synthesis of their roles and interactions within the hippocampal network.