Nandor Ludvig

Cognitive Cell Firing in the Primate Brain
I am interested in the function and regulation of the electrical activity ('firing') of neurons in the primate cognitive system. Specifically, my research focuses on neurons in the hippocampal - association cortical circuitry. In my view, the principal neurons of hippocampus promote the consolidation and orderly connection of space- and time-stamped memory units ('engrams') in the association cortex. I study these neural processes with the combined single-cell recording - intracerebral microdialysis method, in freely moving monkeys. My ultimate goal is to translate the accumulated information into practical use and develop fully implanted, brain-activity controlled intracerebral drug-delivery devices (hybrid neuroprostheses) for the treatment of brain disorders that involve hippocampal - association cortical pathology.

My studies in monkeys have been preceded by studies in freely moving rats. Using a novel experimental paradigm, I demonstrated that rat hippocampal place cells ( a class of pyramidal cells) can flexibly terminate and develop their spatial memory-promoting firing even in a fixed environment, if this environment is explored continuously for a long period (Ludvig, 1999). Based on this finding, and on theoretical considerations, I developed a new theory for the role of hippocampal place cells in memory formation (Fig. 1).

Fig. 1. Panel A: The high frequency discharges of a hippocampal place cell strengthens the synaptic connections within a cell assembly in the association cortex. Via this mechanism, the hippocampal neuron promotes the creation of a permanent spatial engram. Panel B: In the association cortex, the spatial engrams are connected to each other in the temporal order of their creation. This allows the formation of the cognitive map. Yet, this mechanism also allows the encoding of time. Thus, in this model, space and time are encoded with the same cellular mechanism, faithfully representing the external world where space and time are intertwined.

My studies in rats led to the question: Do hippocampal pyramidal cells promote the creation of spatial memories in primates in the same fashion as rat hippocampal place cells? To examine this problem, I developed a method for recording the firing of single neurons from the brain of freely moving monkeys (Ludvig et al., 2001). With this method, it has become possible to monitor the spatial memory-promoting firing of hippocampal pyramidal cells in monkeys during free movement in a 3-dimensional space. It was found that place cells do exist primate hippocampus, although these neurons generate a spatial firing pattern not identical to that of rodent place cells (Fig. 2)

Fig. 2. The spatial firing of a hippocampal pyramidal cell in a rat and that of a hippocampal pyramidal cell in a squirrel monkey. Firing Rate Distribution Maps, developed in collaboration with Lorant Kovacs, ESCO, Garden Grove, CA, are shown. In the map for the rat study, each pixel indicates the average firing rate of the cell in a 9 cm2 area on the rectangular floor of a test chamber, as the rat moved around in two dimensions. In the map for the monkey study, each pixel indicates the average firing rate of the cell in a 90 cm2 area on the floor and in a 230 cm2 area on the walls of a cubic test chamber, as the monkey moved around in three dimensions. The central square represents the floor; the trapezoids represent the walls. Color codes for the firing rates are as indicated; black pixels: highest firing rate; yellow pixels: no firing; white areas: locations not visited by the animal. The rat pyramidal cell functioned as a place cell that increased its firing rate exclusively when the animal’s body was in a particular location (arrow). The monkey pyramidal cell also functioned as a place cell, but it increased its firing rate not only when the animal’s body was in a particular location (arrow), but also when the animal looked at the area of this location from remote sites (see distant black pixels). My interpretation is that with this mechanism monkey hippocampal cells can promote the creation of more complex engrams than rat hippocampal cells. We now examine the firing of these neurons during the performance of a newly developed spatial memory task (Ludvig et al., 2003).

(If you wish to know more about this NSF-funded project titled
Cellular Mechanisms of Encoding Space-Time in the Monkey Brain click here
This site provides you with an update on the progress of the studies.)

These studies opened up the way to examine the molecular/neurochemical regulation of the spatial memory-promoting firing of hippocampal neurons in non-human primates. First, we combined single-cell recording and intracerebral microdialysis methods to monkeys seated in a traditional primate chair (Ludvig et al., 2000). Then, we advanced this technique to be suitable for freely moving monkeys. Fig. 3 shows the results of an experiment with this advanced method. NMDA was delivered, via microdialysis, into the extracellular environment of a hippocampal neuron, while the monkey was moving freely in the test chamber.

Fig. 3. Effect of NMDA on the firing of a monkey hippocampal neuron. Firing rate histogram is shown; X axis: time (min); Y axis: firing rate (spikes/sec). Note the biphasic action of the drug: an initial firing rate increase is followed by electrical silence. From the effects of extracellularly applied drugs on the firing of neurons within the primate cognitive system, we are able to obtain insights into the molecular mechanisms that regulate the electrical activity of these cells.

All behavioral, electrophysiological, pharmacological and histological data collected in these studies, as well as in my previous projects, are being utilized for the development of the hybrid neuroprosthesis (Ludvig, 2000), which I patented (US patent No. 6,497,699; co-developer Lorant Kovacs) in 2002. We are now working on the construction and preclinical testing of the apparatus. For more information, please check the following web-site: hhttp://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=/netahtml/srchnum.htm&r=1&f=G&l=50&s1
=6497699.WKU.&OS=PN/6497699&RS=PN/64976996497699.txt.doc

Selected Publications

Ludvig, N. (1999). Place cells can flexibly terminate and develop their spatial firing. A new theory for their function. Phys. Behav. 67, 56-67.

Ludvig, N., Nguyen, M. C., Botero, J. M., Tang, H. M., Scalia, F., Scharf, B., and Kral, J. G. (2000). Delivering drugs, via microdialysis, into the environment of extracellularly recorded hippocampal neurons in behaving primates. Brain Res. Protocols 5, 75-84.

Ludvig, N. (2000). Drug deliveries into the microenvironment of electrophysiologically monitored neurons in the brain of behaving rats and monkeys. In Neural Prostheses for the Restoration of Sensory and Motor Function (Chapin, J. K., and Moxon, K., eds.), CRC Press, Boca Raton, pp. 263-283.

Ludvig, N., Botero, J. M., Tang, H. M., Gohil, B., and Kral, J. G. (2001). Single-cell recording from the brain of freely moving monkeys. J. Neurosci. Meth. 106, 179-187.

Ludvig, N., Tang, H. M., Eichenbaum, H., and Gohil, B. C. (2003). Spatial memory performance of freely-moving squirrel monkeys. Behav. Brain Res. 140, 175-183.

The above articles are available at: http://scirus.com/ausearch?author=Ludvig+N.&n

Personnel

Hai Michael Tang, M.D., Postdoctoral Fellow

Service Functions

Member of the Editorial Board of Brain Research Protocols.

Member of NIH review group ZRG1 BDCN-1 (1999-2000).