Clifford Kentros

Professor, Kavli Institute for Systems Neuroscience
Member, ION

Ph.D. New York University Medical Center
B.A. New College

 

Research Interests: Cellular and molecular basis of memory.

Overview: What changes in your brain when you learn something?  Lesion studies have determined that a highly conserved structure called the hippocampus is required for memory acquisition in mammals, including humans.  My laboratory is interested in how neurons in the hippocampus and related brain areas reflect experience.  We use two distinct but complementary approaches to this goal:  1) recording neurons from awake, behaving rodents; and 2) generating genetically-modified mice capable of expressing transgenes in particular neuronal cell types relevant to learning and memory.  Combining the former with the latter enables the neural analog of the approach used by engineers to investigate electrical circuits:  basically, one records from one circuit element (i.e. neuronal cell type) while manipulating the activity of others.  In this way we can explore the transformation of information through the circuitry underlying learning and memory.

RECENT PUBLICATIONS

Related Articles

Beyond the bolus: transgenic tools for investigating the neurophysiology of learning and memory.

Learn Mem. 2014 Oct;21(10):506-18

Authors: Lykken C, Kentros CG

Abstract
Understanding the neural mechanisms underlying learning and memory in the entorhinal-hippocampal circuit is a central challenge of systems neuroscience. For more than 40 years, electrophysiological recordings in awake, behaving animals have been used to relate the receptive fields of neurons in this circuit to learning and memory. However, the vast majority of such studies are purely observational, as electrical, surgical, and pharmacological circuit manipulations are both challenging and relatively coarse, being unable to distinguish between specific classes of neurons. Recent advances in molecular genetic tools can overcome many of these limitations, enabling unprecedented control over neural activity in behaving animals. Expression of pharmaco- or optogenetic transgenes in cell-type-specific "driver" lines provides unparalleled anatomical and cell-type specificity, especially when delivered by viral complementation. Pharmacogenetic transgenes are specially designed neurotransmitter receptors exclusively activated by otherwise inactive synthetic ligands and have kinetics similar to traditional pharmacology. Optogenetic transgenes use light to control the membrane potential, and thereby operate at the millisecond timescale. Thus, activation of pharmacogenetic transgenes in specific neuronal cell types while recording from other parts of the circuit allows investigation of the role of those neurons in the steady state, whereas optogenetic transgenes allow one to determine the immediate network response.

PMID: 25225296 [PubMed - indexed for MEDLINE]

Related Articles

Role of self-generated odor cues in contextual representation.

Hippocampus. 2014 Aug;24(8):1039-51

Authors: Aikath D, Weible AP, Rowland DC, Kentros CG

Abstract
As first demonstrated in the patient H.M., the hippocampus is critically involved in forming episodic memories, the recall of "what" happened "where" and "when." In rodents, the clearest functional correlate of hippocampal primary neurons is the place field: a cell fires predominantly when the animal is in a specific part of the environment, typically defined relative to the available visuospatial cues. However, rodents have relatively poor visual acuity. Furthermore, they are highly adept at navigating in total darkness. This raises the question of how other sensory modalities might contribute to a hippocampal representation of an environment. Rodents have a highly developed olfactory system, suggesting that cues such as odor trails may be important. To test this, we familiarized mice to a visually cued environment over a number of days while maintaining odor cues. During familiarization, self-generated odor cues unique to each animal were collected by re-using absorbent paperboard flooring from one session to the next. Visual and odor cues were then put in conflict by counter-rotating the recording arena and the flooring. Perhaps surprisingly, place fields seemed to follow the visual cue rotation exclusively, raising the question of whether olfactory cues have any influence at all on a hippocampal spatial representation. However, subsequent removal of the familiar, self-generated odor cues severely disrupted both long-term stability and rotation to visual cues in a novel environment. Our data suggest that odor cues, in the absence of additional rule learning, do not provide a discriminative spatial signal that anchors place fields. Such cues do, however, become integral to the context over time and exert a powerful influence on the stability of its hippocampal representation.

PMID: 24753119 [PubMed - indexed for MEDLINE]

Related Articles

Transgenically targeted rabies virus demonstrates a major monosynaptic projection from hippocampal area CA2 to medial entorhinal layer II neurons.

J Neurosci. 2013 Sep 11;33(37):14889-98

Authors: Rowland DC, Weible AP, Wickersham IR, Wu H, Mayford M, Witter MP, Kentros CG

Abstract
The enormous potential of modern molecular neuroanatomical tools lies in their ability to determine the precise connectivity of the neuronal cell types comprising the innate circuitry of the brain. We used transgenically targeted viral tracing to identify the monosynaptic inputs to the projection neurons of layer II of medial entorhinal cortex (MEC-LII) in mice. These neurons are not only major inputs to the hippocampus, the structure most clearly implicated in learning and memory, they also are "grid cells." Here we address the question of what kinds of inputs are specifically targeting these MEC-LII cells. Cell-specific infection of MEC-LII with recombinant rabies virus results in unambiguous labeling of monosynaptic inputs. Furthermore, ratios of labeled neurons in different regions are largely consistent between animals, suggesting that label reflects density of innervation. While the results mostly confirm prior anatomical work, they also reveal a novel major direct input to MEC-LII from hippocampal pyramidal neurons. Interestingly, the vast majority of these direct hippocampal inputs arise not from the major hippocampal subfields of CA1 and CA3, but from area CA2, a region that has historically been thought to merely be a transitional zone between CA3 and CA1. We confirmed this unexpected result using conventional tracing techniques in both rats and mice.

PMID: 24027288 [PubMed - indexed for MEDLINE]

Related Articles

Neural correlates of long-term object memory in the mouse anterior cingulate cortex.

J Neurosci. 2012 Apr 18;32(16):5598-608

Authors: Weible AP, Rowland DC, Monaghan CK, Wolfgang NT, Kentros CG

Abstract
Damage to the hippocampal formation results in a profound temporally graded retrograde amnesia, implying that it is necessary for memory acquisition but not its long-term storage. It is therefore thought that memories are transferred from the hippocampus to the cortex for long-term storage in a process called systems consolidation (Dudai and Morris, 2000). Where in the cortex this occurs remains an open question. Recent work (Frankland et al., 2005; Vetere et al., 2011) suggests the anterior cingulate cortex (ACC) as a likely candidate area, but there is little direct electrophysiological evidence to support this claim. Previously, we demonstrated object-associated firing correlates in caudal ACC during tests of recognition memory and described evidence of neuronal responses to where an object had been following a brief delay. However, long-term memory requires evidence of more durable representations. Here we examined the activity of ACC neurons while testing for long-term memory of an absent object. Mice explored two objects in an arena and then were returned 6 h later with one of the objects removed. Mice continued to explore where the object had been, demonstrating memory for that object. Remarkably, some ACC neurons continued to respond where the object had been, while others developed new responses in the absent object's location. The incidence of absent-object responses by ACC neurons was greatly increased with increased familiarization to the objects, and such responses were still evident 1 month later. These data strongly suggest that the ACC contains neural correlates of consolidated object/place association memory.

PMID: 22514321 [PubMed - indexed for MEDLINE]

Related Articles

A stable hippocampal representation of a space requires its direct experience.

Proc Natl Acad Sci U S A. 2011 Aug 30;108(35):14654-8

Authors: Rowland DC, Yanovich Y, Kentros CG

Abstract
In humans and other mammals, the hippocampus is critical for episodic memory, the autobiographical record of events, including where and when they happen. When one records from hippocampal pyramidal neurons in awake, behaving rodents, their most obvious firing correlate is the animal's position within a particular environment, earning them the name "place cells." When an animal explores a novel environment, its pyramidal neurons form their spatial receptive fields over a matter of minutes and are generally stable thereafter. This experience-dependent stabilization of place fields is therefore an attractive candidate neural correlate of the formation of hippocampal memory. However, precisely how the animal's experience of a context translates into stable place fields remains largely unclear. For instance, we still do not know whether observation of a space is sufficient to generate a stable hippocampal representation of that space because the animal must physically visit a spot to demonstrate which cells fire there. We circumvented this problem by comparing the relative stability of place fields of directly experienced space from merely observed space following blockade of NMDA receptors, which preferentially destabilizes newly generated place fields. This allowed us to determine whether place cells stably represent parts of the environment the animal sees, but does not actually occupy. We found that the formation of stable place fields clearly requires direct experience with a space. This suggests that place cells are part of an autobiographical record of events and their spatial context, consistent with providing the "where" information in episodic memory.

PMID: 21852575 [PubMed - indexed for MEDLINE]

Related Articles

Transgenic targeting of recombinant rabies virus reveals monosynaptic connectivity of specific neurons.

J Neurosci. 2010 Dec 8;30(49):16509-13

Authors: Weible AP, Schwarcz L, Wickersham IR, Deblander L, Wu H, Callaway EM, Seung HS, Kentros CG

Abstract
Understanding how neural circuits work requires a detailed knowledge of cellular-level connectivity. Our current understanding of neural circuitry is limited by the constraints of existing tools for transsynaptic tracing. Some of the most intractable problems are a lack of cellular specificity of uptake, transport across multiple synaptic steps conflating direct and indirect inputs, and poor labeling of minor inputs. We used a novel combination of transgenic mouse technology and a recently developed tracing system based on rabies virus (Wickersham et al., 2007a,b) to overcome all three constraints. Because the virus requires transgene expression for both initial infection and subsequent retrograde transsynaptic infection, we created several lines of mice that express these genes in defined cell types using the tetracycline-dependent transactivator system (Mansuy and Bujard, 2000). Fluorescent labeling from viral replication is thereby restricted to defined neuronal cell types and their direct monosynaptic inputs. Because viral replication does not depend on transgene expression, it provides robust amplification of signal in presynaptic neurons regardless of input strength. We injected virus into transgenic crosses expressing the viral transgenes in specific cell types of the hippocampus formation to demonstrate cell-specific infection and monosynaptic retrograde transport of virus, which strongly labels even minor inputs. Such neuron-specific transgenic complementation of recombinant rabies virus holds great promise for obtaining cellular-resolution wiring diagrams of the mammalian CNS.

PMID: 21147990 [PubMed - indexed for MEDLINE]

Related Articles

Potential anatomical basis for attentional modulation of hippocampal neurons.

Ann N Y Acad Sci. 2008;1129:213-24

Authors: Rowland DC, Kentros CG

Abstract
Lesions of the hippocampus and related structures produce profound anterograde amnesia. The amnesia is specific to what has been called "explicit," "declarative," and "episodic" memory. These memories are frequently believed to be central to the human condition, requiring such advanced cognitive functions as attention and even consciousness. However, the hippocampus and associated structures are evolutionarily conserved, which argues that the memories of lower mammals should be qualitatively similar in nature. Just as attention and arousal are critical components of appropriate memory formation in humans, an emerging body of evidence suggests that these processes bear on the firing patterns of hippocampal neurons in rodents. Here the evidence favoring this hypothesis is discussed and then the potential anatomical basis for such modulation is considered.

PMID: 18591482 [PubMed - indexed for MEDLINE]

Related Articles

State-dependent alterations in hippocampal oscillations in serotonin 1A receptor-deficient mice.

J Neurosci. 2005 Jul 13;25(28):6509-19

Authors: Gordon JA, Lacefield CO, Kentros CG, Hen R

Abstract
Mice lacking the serotonin 1A receptor (5-HT(1A)R) show increased levels of anxiety-related behavior across multiple tests and background strains. Tissue-specific rescue experiments, lesion studies, and neurophysiological findings all point toward the hippocampus as a potential mediator of the phenotype. Serotonin, acting through 5-HT(1A)Rs, can suppress hippocampal theta-frequency oscillations, suggesting that theta oscillations might be increased in the knock-outs. To test this hypothesis, local field potential recordings were obtained from the hippocampus of awake, behaving knock-outs and wild-type littermates. The magnitude of theta oscillations was increased in the knock-outs, specifically in the anxiety-provoking elevated plus maze and not in a familiar environment or during rapid eye movement sleep. Theta power correlated with the fraction of time spent in the open arms, an anxiety-related behavioral variable. These results suggest a possible role for the hippocampus, and theta oscillations in particular, in the expression of anxiety in 5-HT(1A)R-deficient mice.

PMID: 16014712 [PubMed - indexed for MEDLINE]