Genetic control of active neural circuits - PubMed (original) (raw)

Genetic control of active neural circuits

Leon Reijmers et al. Front Mol Neurosci. 2009.

Abstract

The use of molecular tools to study the neurobiology of complex behaviors has been hampered by an inability to target the desired changes to relevant groups of neurons. Specific memories and specific sensory representations are sparsely encoded by a small fraction of neurons embedded in a sea of morphologically and functionally similar cells. In this review we discuss genetics techniques that are being developed to address this difficulty. In several studies the use of promoter elements that are responsive to neural activity have been used to drive long-lasting genetic alterations into neural ensembles that are activated by natural environmental stimuli. This approach has been used to examine neural activity patterns during learning and retrieval of a memory, to examine the regulation of receptor trafficking following learning and to functionally manipulate a specific memory trace. We suggest that these techniques will provide a general approach to experimentally investigate the link between patterns of environmentally activated neural firing and cognitive processes such as perception and memory.

Keywords: amygdala; creb; fear conditioning; fos; genetics; memory; neural circuits; tetracycline.

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Figures

Figure 1

Figure 1

Clustered and distributed neural ensembles. Two examples of neural circuits are shown. The top panel shows a simplified version of the gill and siphon withdrawal circuit in Aplysia. The sensory neuron cell bodies are located adjacent to each other in a cluster and possess similar biochemistry and response properties. The bottom panel represents the hippocampal circuit of the mammalian brain. The green circles represent neurons that are activated by a specific pattern of sensory stimulation and that when activated contribute to a specific behavioral response. The hippocampal circuit, like many other circuits in the brain, responds to sensory stimulation with activation patterns that can not be predicted from their wiring diagram. Each of these neural ensembles involves a sparse subset of neurons that have an unpredictable spatial distribution. The Aplysia neurons are primary sensory neurons and their response properties can be predicted by their physical location in the ganglion.

Figure 2

Figure 2

The TetTag mouse. The figure summarizes an experiment from Reijmers et al. (2007). Mice carrying two transgenes were used. The first transgene uses the cfos promoter to drive expression of the tetracycline transactivator (tTA). tTA activates the tetO promoter in the absence but not presence of doxycycline (Dox). The second transgene uses the tetO promoter to drive expression of a Dox insensitive tTA (tTA*), which, once expressed, sets up a positive feedback loop that continuously drives expression of a β-galactosidase reporter coupled to the tau protein (taulacZ). Neurons activated during fear conditioning (while off Dox) were tagged with long-lasting expression of taulacZ (LAC; red circle). Mice were put back on food with doxycycline and a retrieval test was done 3 days later, followed by analysis of the brains 1 h after retrieval for expression of lacZ and zif268. Neurons activated during learning expressed lacZ and those active during retrieval expressed zif268 (ZIF; green circle). The number of neurons in the amygdala that expressed both LAC and ZIF, indicating that they were activate during both learning and retrieval, was positively correlated with the strength of the fear memory that the animal displayed.

Figure 3

Figure 3

Disrupting a specific memory in the mouse. The figure summarizes the experiments of Han et al. (2009). Transgenic mice were used that express an inducible diphtheria toxin receptor (iDTR). A viral vector expressing both CREB and CRE recombinase was injected into the amygdala of iDTR mice leading to the expression of both CRE and CREB in a random subset of neurons (circles with CREB/CRE). The CRE recombinase removed a transcriptional STOP sequence and allowed for expression of DTR in these CREB expressing neurons. The mice were then subjected to fear conditioning. An earlier study from the same authors (Han et al., 2007) demonstrated that the CREB expressing neurons participate in the storage of the fear memory (green circles symbolize neurons that participate in the storage of the memory). After fear conditioning, mice were injected with diphtheria toxin (DT), which killed the CREB expressing neurons which participated in the encoding of that memory (red circles). This caused a significant reduction in the strength of the fear memory measured during retrieval.

Figure 4

Figure 4

Learning regulated targeting of glutamate receptors. The figure summarizes an experiment from Matsuo et al. (2008). Mice carrying two transgenes were used. The first transgene is identical to the one described in Figure 2 and uses the cfos promoter to drive expression of a tetracycline transactivator (tTA). The second transgene was a tetO-promoter GFP tagged glutamate receptor subunit (GluR1-GFP). Animals were fear conditioned in the absence of Dox to produce both a fear memory and a pulse of GFP-GluR1 expression in active neural ensembles in the hippocampus. The distribution of GFP-GluR1 in dendritic spines was analyzed 24 h following the conditioning using DiI to label all spines on a given neuron. Fear conditioning led to an increase in trafficking of the receptor specifically to mushroom type spines. This experiment demonstrates how genetic tools can be used to image a specific molecular event selectively within an activated neural circuit.

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