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    Loren Frank, PhD

    TitleProfessor
    SchoolUCSF School of Medicine
    DepartmentPhysiology
    Address675 Nelson Rising Lane
    San Francisco CA 94143
    Phone415-502-7357

       Overview 
       Overview
      Research Overview

      The ability to store experiences and then use them to guide behavior is one of the most remarkable abilities of the brain. Our goal is to understand how activity and plasticity in neural circuits underlie both learning and the ability to use learned information to make decisions. In particular, our laboratory focuses on the circuitry of the hippocampus and anatomically related regions. We use a combination of techniques, including large scale multielectrode recording, targeted optogenetic interventions and behavioral manipulations of awake, behaving animals to understand how the brain learns and remembers.

      Learning in the Hippocampus and Cortex

      Previous studies have shown that neurons throughout the hippocampal formation show place specific firing patterns, where a given neuron is active only in a subregion of the animal's environment. Most of these studies focused on describing patterns of activity during well learned tasks, and we therefore know little about neural processing during learning. We have developed a spatial alternation task that animals can learn over the course of a few days of exposure. We have shown that rapid learning in this task requires an intact hippocampus, and thus this task provides a powerful paradigm for examining the relationship between dynamic patterns of neural activity and changes in behavior.

      Although the hippocampus is essential for spatial learning, storing and retrieving new information requires complex networks spread throughout the brain. One prominent hypothesis states that learning takes place first in the hippocampus and over time information is transferred to neocortical regions in a process known as consolidation. We are therefore recording both in the hippocampus and in downstream areas to understand how hippocampal and cortical circuits could support learning, consolidation and memory guided behavior.

      These studies continue to provide important new insights into how the brain changes as animals learn and how memory retrieval might occur, but these insights are fundamentally correlational in nature. We have therefore been developing and apply new techniques, including optogenetic manipulations, to take these correlational hypothesis and turn them into causal understanding. We can now express optically activated channels in specific subpopulations of neurons in the rat hippocampus and activate these channels with an implanted fiber optic. We have also combined this optical activation with large scale multielectrode recording, allowing us to manipulate the circuit and record the results both locally and in more distant brain regions.
      Anatomical Organization of the Hippocampus

      The hippocampal formation has a unique anatomical organization in that the connectivity between adjacent hippocampal regions is almost exclusively unidirectional. The majority of neocortical input to the hippocampus comes in through the superficial layers of the entorhinal cortex and connections proceed through the dentate gyrus, to CA3 and on to CA1 (the hippocampus proper), and then to the subiculum. Nearly all neocortically bound outputs from the hippocampus originate in CA1 and the subiculum and target cells in the deep layers of the entorhinal cortex, which projects both to numerous neocortical regions as well as to back to the superficial layers of the entorhinal cortex. Our research uses that organization to compare patterns of activity across regions and to use the similarities and differences among the patterns to identify the transformations that occur in the hippocampal circuit.

      An Animal Model for Hippocampal Function

      Numerous researchers have shown that a human without a hippocampus is unable to form new memories of facts or events. In rodents these same structures play an essential role in animal's abilities to learn about and remember complex associations, including tasks where the animal must learn and remember information about a set of spatial cues in order to navigate through an environment. Event/fact memory in humans and spatial memory in rodents both require learning complex relationships, and that parallel strongly suggests that qualitatively similar processing occurs in the human and the rat hippocampus.


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       Bibliographic 
       Publications
      Publications listed below are automatically derived from MEDLINE/PubMed and other sources, which might result in incorrect or missing publications. Researchers can login to make corrections and additions, or contact us for help.
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      1. Dabaghian Y, Brandt VL, Frank LM. Reconceiving the hippocampal map as a topological template. Elife. 2014; 3:e03476.
        View in: PubMed
      2. Larkin MC, Lykken C, Tye LD, Wickelgren JG, Frank LM. Hippocampal output area CA1 broadcasts a generalized novelty signal during an object-place recognition task. Hippocampus. 2014 Jul; 24(7):773-83.
        View in: PubMed
      3. Felix SH, Shah KG, Tolosa VM, Sheth HJ, Tooker AC, Delima TL, Jadhav SP, Frank LM, Pannu SS. Insertion of flexible neural probes using rigid stiffeners attached with biodissolvable adhesive. J Vis Exp. 2013; (79):e50609.
        View in: PubMed
      4. Kemere C, Carr MF, Karlsson MP, Frank LM. Rapid and continuous modulation of hippocampal network state during exploration of new places. PLoS One. 2013; 8(9):e73114.
        View in: PubMed
      5. Singer AC, Carr MF, Karlsson MP, Frank LM. Hippocampal SWR activity predicts correct decisions during the initial learning of an alternation task. Neuron. 2013 Mar 20; 77(6):1163-73.
        View in: PubMed
      6. Warden MR, Selimbeyoglu A, Mirzabekov JJ, Lo M, Thompson KR, Kim SY, Adhikari A, Tye KM, Frank LM, Deisseroth K. A prefrontal cortex-brainstem neuronal projection that controls response to behavioural challenge. Nature. 2012 Dec 20; 492(7429):428-32.
        View in: PubMed
      7. Carr MF, Karlsson MP, Frank LM. Transient slow gamma synchrony underlies hippocampal memory replay. Neuron. 2012 Aug 23; 75(4):700-13.
        View in: PubMed
      8. Kim SM, Ganguli S, Frank LM. Spatial information outflow from the hippocampal circuit: distributed spatial coding and phase precession in the subiculum. J Neurosci. 2012 Aug 22; 32(34):11539-58.
        View in: PubMed
      9. Shinnar S, Bello JA, Chan S, Hesdorffer DC, Lewis DV, Macfall J, Pellock JM, Nordli DR, Frank LM, Moshe SL, Gomes W, Shinnar RC, Sun S. MRI abnormalities following febrile status epilepticus in children: the FEBSTAT study. Neurology. 2012 Aug 28; 79(9):871-7.
        View in: PubMed
      10. Jadhav SP, Kemere C, German PW, Frank LM. Awake hippocampal sharp-wave ripples support spatial memory. Science. 2012 Jun 15; 336(6087):1454-8.
        View in: PubMed
      11. Carr MF, Frank LM. A single microcircuit with multiple functions: state dependent information processing in the hippocampus. Curr Opin Neurobiol. 2012 Aug; 22(4):704-8.
        View in: PubMed
      12. Anikeeva P, Andalman AS, Witten I, Warden M, Goshen I, Grosenick L, Gunaydin LA, Frank LM, Deisseroth K. Optetrode: a multichannel readout for optogenetic control in freely moving mice. Nat Neurosci. 2012 Jan; 15(1):163-70.
        View in: PubMed
      13. Li JX, Medina JF, Frank LM, Lisberger SG. Acquisition of neural learning in cerebellum and cerebral cortex for smooth pursuit eye movements. J Neurosci. 2011 Sep 7; 31(36):12716-26.
        View in: PubMed
      14. Carr MF, Jadhav SP, Frank LM. Hippocampal replay in the awake state: a potential substrate for memory consolidation and retrieval. Nat Neurosci. 2011 Feb; 14(2):147-53.
        View in: PubMed
      15. Smith AC, Nguyen VK, Karlsson MP, Frank LM, Smith P. Probability of repeating patterns in simultaneous neural data. Neural Comput. 2010 Oct; 22(10):2522-36.
        View in: PubMed
      16. Singer AC, Karlsson MP, Nathe AR, Carr MF, Frank LM. Experience-dependent development of coordinated hippocampal spatial activity representing the similarity of related locations. J Neurosci. 2010 Sep 1; 30(35):11586-604.
        View in: PubMed
      17. Singer AC, Frank LM. Rewarded outcomes enhance reactivation of experience in the hippocampus. Neuron. 2009 Dec 24; 64(6):910-21.
        View in: PubMed
      18. Jadhav SP, Frank LM. Reactivating memories for consolidation. Neuron. 2009 Jun 25; 62(6):745-6.
        View in: PubMed
      19. Karlsson MP, Frank LM. Awake replay of remote experiences in the hippocampus. Nat Neurosci. 2009 Jul; 12(7):913-8.
        View in: PubMed
      20. Kim SM, Frank LM. Hippocampal lesions impair rapid learning of a continuous spatial alternation task. PLoS One. 2009; 4(5):e5494.
        View in: PubMed
      21. Karlsson MP, Frank LM. Network dynamics underlying the formation of sparse, informative representations in the hippocampus. J Neurosci. 2008 Dec 24; 28(52):14271-81.
        View in: PubMed
      22. Cheng S, Frank LM. New experiences enhance coordinated neural activity in the hippocampus. Neuron. 2008 Jan 24; 57(2):303-13.
        View in: PubMed
      23. Frank LM, Brown EN, Stanley GB. Hippocampal and cortical place cell plasticity: implications for episodic memory. Hippocampus. 2006; 16(9):775-84.
        View in: PubMed
      24. Law JR, Flanery MA, Wirth S, Yanike M, Smith AC, Frank LM, Suzuki WA, Brown EN, Stark CE. Functional magnetic resonance imaging activity during the gradual acquisition and expression of paired-associate memory. J Neurosci. 2005 Jun 15; 25(24):5720-9.
        View in: PubMed
      25. Barbieri R, Wilson MA, Frank LM, Brown EN. An analysis of hippocampal spatio-temporal representations using a Bayesian algorithm for neural spike train decoding. IEEE Trans Neural Syst Rehabil Eng. 2005 Jun; 13(2):131-6.
        View in: PubMed
      26. Frank LM, Stanley GB, Brown EN. Hippocampal plasticity across multiple days of exposure to novel environments. J Neurosci. 2004 Sep 1; 24(35):7681-9.
        View in: PubMed
      27. Eden UT, Frank LM, Barbieri R, Solo V, Brown EN. Dynamic analysis of neural encoding by point process adaptive filtering. Neural Comput. 2004 May; 16(5):971-98.
        View in: PubMed
      28. Barbieri R, Frank LM, Nguyen DP, Quirk MC, Solo V, Wilson MA, Brown EN. Dynamic analyses of information encoding in neural ensembles. Neural Comput. 2004 Feb; 16(2):277-307.
        View in: PubMed
      29. Smith AC, Frank LM, Wirth S, Yanike M, Hu D, Kubota Y, Graybiel AM, Suzuki WA, Brown EN. Dynamic analysis of learning in behavioral experiments. J Neurosci. 2004 Jan 14; 24(2):447-61.
        View in: PubMed
      30. Nathe AR, Frank LM. Making space for rats: from synapse to place code. Neuron. 2003 Aug 28; 39(5):730-1.
        View in: PubMed
      31. Frank LM, Brown EN. Persistent activity and memory in the entorhinal cortex. Trends Neurosci. 2003 Aug; 26(8):400-1.
        View in: PubMed
      32. Wirth S, Yanike M, Frank LM, Smith AC, Brown EN, Suzuki WA. Single neurons in the monkey hippocampus and learning of new associations. Science. 2003 Jun 6; 300(5625):1578-81.
        View in: PubMed
      33. Nguyen DP, Frank LM, Brown EN. An application of reversible-jump Markov chain Monte Carlo to spike classification of multi-unit extracellular recordings. Network. 2003 Feb; 14(1):61-82.
        View in: PubMed
      34. Frank LM, Eden UT, Solo V, Wilson MA, Brown EN. Contrasting patterns of receptive field plasticity in the hippocampus and the entorhinal cortex: an adaptive filtering approach. J Neurosci. 2002 May 1; 22(9):3817-30.
        View in: PubMed
      35. Brown EN, Barbieri R, Ventura V, Kass RE, Frank LM. The time-rescaling theorem and its application to neural spike train data analysis. Neural Comput. 2002 Feb; 14(2):325-46.
        View in: PubMed
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