Neurotransmitter receptors

The thalamus has been traditionally viewed as a structural relay to specific cortical
areas behaviorally associated with sensory or motor functions, and thalamic nuclei that
function in this manner are referred to as 'relay nuclei·. However. the parts of the
thalamus interconnecting limbic association cortices (functionally involved in memory.
reward, emotion. and decision making) comprise the midline and intralaminar nuclei. The
midline thalamus has not been examined fully at the anatomical, physiological. or
behavioral level, and may serve as an important relay between cortical and subcortical
structures and the limbic system. The work incorporated into this dissertation included
five axonal tract tracing projects that were conducted in the rat. to explore and test the
hypothesis that the midline thalamus serves as an important interface between limbic
structures including the amygdala. nucleus accumbens. medial prefrontal cortex and
hippocampal formation.
An important finding was the demonstration of a closed anatomical loop between the
hippocampal formation, the ventral medial prefrontal cortex and the ventral midline
thalamus: CA 1/subiculum > PLIIL > RE > CA 1/subiculum. Another finding was that 1) the hippocampal formation innervates the entire medial prefrontal cortex; and 2) the
hippocampal formation projects more heavily to ventral as compared to dorsal cortices in
the mPFC. The paraventricular, parataenial, rhomboid and reuniens nuclei of the midline
thalamus were shown to distribute to limbic structures important for cognitive
processing: the amygdala, nucleus accumbens, hippocampal formation, parahippocampal
cortex, and the prefrontal cortex. Present results demonstrate that the ventral midline
nuclei (reuniens and rhomboid) extensively innervate limbic cortical structures (the
medial prefrontal cortex and hippocampal formation) whereas dorsal midline nuclei
(paraventricular and parataenial) distribute more heavily to subcortical limbic structures
(the amygdala and the nucleus accumbens). These midline nuclei may, therefore, relay
information between these limbic areas. This connectivity suggests that the midline
nuclei could further be subdivided from the intralaminar and relay groups. The midline
thalamic nuclei would, therefore, comprise the limbic thalamus.

In this dissertat ion, the early visual system is used to explore the role of efficiency in
the general organization of the nervous system. Efficient representation theory predicts
that neurons dynamically change their responses to changes in the environment in order to
maintain their efficiency. To directly test the predication of this theory, a computational
model and a neurophysiological experiment are used. Using a computational model, we investigate the sparseness of the response of filters at
each stage of the model of the visual pathway. We find that the temporal bandpass filter
and the rectification in each stage improves the efficiency of the response representation.
Moreover, we find that ON/nonlagged responses carry more information than OFF/ lagged
responses in signals with low signal-to-noise ratios. In the neurophysiological experiment, the response of LGN cells is measured and compared
to their input from the retina in awake cats during free-viewing of natural time-varying
images using quasi-intracellular recording technique. We find that the neural responses in
the retina and the LGN are efficient. However, the LGN response is more efficient, sparser and less correlated than the retina's response, and it carries less information about eye
movements than the retina's. As a result the LGN represents the visual world with fewer
spikes. The LGN response changes with the variation of visual input. The temporal correlation
of the visual input changes with saccade timing. Accordingly, the temporal receptive field of
the LGN also changes in order to maintain the decorrelation of the LGN response regardless
of the saccade. The retina-thalamic transmission changes during and after a saccade in order to transmit
useful information to the visual cortex and decreases during a saccade in order to eliminate
the variation of the visual input during a saccade. However, the transmission increases after
a saccade to facilitate the transmission of new information due to the new gaze direction in
the visual environment. The temporal receptive field of the LGN, derived from the efficacy of the thalamic
transmission, is causal and bimodal. Such a receptive field decorrelates the visual input
and improves the sparseness of the LGN response representation.

It is of interest to understand how new neurons incorporate themselves into the
existing circuitry of certain neuronal populations. One such population of neurons is that
which are born in the subventricular zone (SVZ) and migrate to the olfactory bulb where
they differentiate into granule cells. Another area of interest is the role of brain-derived
neurotrophic factor (BDNF) on the survival and overall health of these neurons. This
study aimed to test whether or not BDNF is a survival factor for adult-born granule cells.
Here were utilized a transgenic mouse model over-expressing BDNF under the α-
calcium/calmodulin-dependent protein kinase II (CAMKIIα) promoter, and tested its
effect on olfactory granule cells under sensory deprived conditions. Results from this
experiment indicated that there was no significant difference in cell death or cell survival when comparing transgenic and wild type animals. We concluded that BDNF is not a
survival factor for adult-born granule cells.

SK channels are small conductance Ca2+-activated K+ channels expressed throughout the CNS. SK channels modulate the excitability of hippocampal CA1 neurons by affecting afterhyperpolarization and shaping excitatory postsynaptic responses. Such SK-mediated effects on activity-dependent neuronal excitability and synaptic strength are thought to underlie the modulatory influence of SK channels on memory encoding. Here,the effect of a new SK1 selective activator, GW542573X, on hippocampal-dependent object memory, contextual and cued conditioning, and trace fear conditioning was examined. The results demonstrated that pre- but not post-training systemic administration of GW542573X impaired object memory and trace fear memory in mice 24 h after training. Contextual and cued fear memory were not disrupted. These current data suggest that activation of SK1 subtype-containing SK channels impairs long-term memory. These results are consistent with converging evidence that SK channel activation suppressed behaviorally triggered synaptic plasticity necessary for encoding hippocampal-dependent memory.

Olfactory sensory neurons (OSN) expressing the same odor receptor (OR) project their axons to topographically fixed glomeruli in the olfactory bulb (OB). This topographic map results from axon guidance mechanisms determined by ORs, glia and molecular guidance cues. The present study examined the organization of mature OSNs expressing the P2 OR in adult mice after ablation of bulb neurons with N-methyl-D-aspartate (NMDA). Rapid neuronal degeneration was followed by progressive laminar disorganization of the OB and glomerular shrinkage. P2 axon targeting and convergence was maintained within degenerating glomeruli for up to 2 weeks. After that time, fewer P2 axons were observed in the lesioned OB with fewer P2 neurons in the olfactory epithelium (OE). By 3 weeks, the mature OSN population was reduced and the immature population was increased. These results suggest that bulbar synaptic contacts do not maintain sensory axon convergence in the adult, but regulate neuronal survival in the OE.

The rodent hippocampus is critical for processing spatial memory but its contribution to non-spatial, specifically object memory is debated. The cognitive map theory of hippocampal function states that the hippocampus stores relationships of goal locations (places) to discrete items (objects) encountered within environments. Dorsal CA1 place cells were recorded in male C57BL/6J mice performing three variations of the novel object recognition paradigm to define "object-in-context" representation of hippocampal neuronal activity that may support object memory. Results indicate, (i) that place field stability is higher when polarizing environmental cues are provided during object recognition; (ii) hippocampal place fields remain stable throughout the novel object recognition testing without a polarizing cue; and (iii) time dependent effects on stability when objects were dissociated from the context. These data indirectly support that the rodent hippocampus processes object memory, and challenge the view that "object-in-context" representations are formed when mice perform novel object recognition task.

Acupuncture has been used for thousands of years to treat a wide range of diseases, but the mechanisms involved in the process have remained a mystery. The present study measures EEG responses to stimulation of a specific acupuncture point, GB37 (Guang Ming), with two different types of manual needle stimulation. Previous studies stimulated for a maximum of 2 minutes. The present study reflects the normal acupuncture treatment time of 20 minutes, with EEG recordings during and for 10 minutes prior to and after stimulation. Our results show no changes in the global spatial and temporal properties of EEG during and shortly after acupuncture treatment of acupoint GB37. The second part of this study examines the global protein expression of glutamic acid decarboxylase (GAD) knockout mice. GAD is the rate-limiting enzyme in the synthesis of GABA, the major inhibitory neurotransmitter in the brain. The protein content of wild type, hetero-, and homozygous GAD knockout mice brains were determined using a LC-MS-based gel-free shotgun profiling of complex protein mixtures. The data was analyzed using the Raculovic algorithm to determine the proteins differences. A short list of 32 proteins was determined with four that have been shown to be significant proteins that influence cell survival and excitotoxicity in the brain and have potential relationships with GABA. These proteins include VATPase, Glutamine synthetase, Beta-synuclein, and Micortuble associated protein (MAP). The proteomics results provide a preliminary best guess list of proteins influencing GAD and GABA production.

Serotonin (5-HT) is a neurotransmitter in the central nervous system. Decrease in the brain 5-HT level could induce depression, showing a state of low mood, aversion to motion and feeling of worthlessness. About 12 million adults in the United States have depression. Antidepressants, such as monoamine oxidase inhibitors and selective serotonin reuptake inhibitors, can alleviate the depressive mood by increasing the brain's 5-HT activity, however they can also induce a potentially life-threatening side effect, namely 5-HT syndrome. This syndrome is manifested by neuromuscular hyperactivities, mental disorders and autonomic dysfunctions. Clinical studies have demonstrated that 5-HT2A receptor antagonists could effectively block severe symptoms of patients with the 5-HT syndrome. To understand the underlying mechanisms, in this study we examined the activity of the 5-HT2A receptor in rats with the 5-HT syndrome evoked by a combined injection of clorgyline, a monoamine oxidase inhibitor , and paroxetine, a selective 5-HT reuptake inhibitor. The major findings from my study were that: (1) Chronic clorgyline treatment significantly exacerbated 5-HT2A receptor-mediated symptoms of the 5-HT syndrome animals; (2) The 5-HT2A receptor-mediated symptoms were also aggravated when the 5-HT syndrome animals were housed in warm (32 ÀC) ambient temperature; (3) Blocking 5-HT2A receptors in the medial prefrontal cortex alleviated the 5-HT syndrome through a circuit between raphe serotonergic neurons and medial prefrontal cortex glutamatergic neurons. Taken together, my data demonstrate that the activity of 5-HT2A receptors may be enhanced by chronic antidepressant treatment and warm environmental temperature.

Serotonin syndrome (SS) is a drug-induced toxicity caused by an excess of serotonin (5-HT) in the central nervous system (CNS). The symptoms of the disorder range from mild to severe, with the severe state evoking life-threatening hyperthermia. Autonomic dysfunction is controlled in part by serotonin receptors, with the 5-HT2A receptor responsible for increasing core body temperature (Tcor). Our results show that the 5-HT2A receptors on the preoptic/anterior hypothalamus (PO/AH) and prefrontal cortex (PFC), in particular, are sensitive to changes in ambient temperature (Tamb). The toxic increase of 5-HT is postulated to occur due to the temperature-dependent activation of these receptors that promotes a positive feedback mechanism. Our results suggest that changes in Tamb can either exacerbate or alleviate the symptom and that this is mediated by the 5-HT2A receptors. Understanding the mechanism involved in elevating Tcor is imperative in treating and preventing the disorder.

New neurons are continuously generated in the olfactory system of adult mice, including olfactory sensory neurons (OSNs) in the olfactory epithelium (OE) and interneurons, produced in the subventricular zone (SVZ) and migrated toward olfactory bulb (OB) along rostral migratory stream (RMS). The present study observed the effects of target neuron loss on the life-span and maturation of adult-born OSNs in the OE and on the proliferation, migration and differentiation of SVZ stem cells in the forebrain after eliminating bulb neurons. We found the life-span of newborn neurons in the absence of synaptic targets was shortened, but the timing of maturation was not delayed. In addition, SVZ cells continued to divide and migrate to the damaged bulb, and the migration of newborn cells in the RMS on the contralateral side was delayed at 2 weeks post-BrdU. Also, the proliferation of cells in dentate gyrus of the hippocampus was not affected by OB damage at 3 weeks post-lesion, though lesion affects occurred in the adult SVZ/RMS.