Biomedical subjects

Susan R Sesack

Publications and source records attributed to Susan R Sesack.

12 recordsLinked to original sources

PubMed2006

Cholinergic axons in the rat ventral tegmental area synapse preferentially onto mesoaccumbens dopamine neurons.

Cholinergic afferents to the ventral tegmental area (VTA) contribute substantially to the regulation of motivated behaviors and the rewarding properties of nicotine. These actions are believed to involve connections with dopamine (DA) neurons projecting to the nucleus accumbens (NAc). However, this direct synaptic link has never been investigated, nor is it known whether cholinergic inputs innervate other populations of DA and gamma-aminobutyric acid (GABA) neurons, including those projecting to the prefrontal cortex (PFC). We addressed these questions by using electron microscopic analysis of retrograde tract-tracing and immunocytochemistry for the vesicular acetylcholine transporter (VAChT) and for tyrosine hydroxylase (TH) and GABA. In tissue labeled for TH, VAChT(+) terminals frequently synapsed onto DA mesoaccumbens neurons but only seldom contacted DA mesoprefrontal cells. In tissue labeled for GABA, one-third of VAChT(+) terminals innervated GABA-labeled dendrites, including both mesoaccumbens and mesoprefrontal populations. VAChT(+) synapses onto DA and mesoaccumbens neurons were more commonly of the asymmetric (presumed excitatory) morphological type, whereas VAChT(+) synapses onto GABA cells were more frequently symmetric (presumed inhibitory or modulatory). These findings suggest that cholinergic inputs to the VTA mediate complex synaptic actions, with a major portion of this effect likely to involve an excitatory influence on DA mesoaccumbens neurons. As such, the results suggest that natural and drug rewards operating through cholinergic afferents to the VTA have a direct synaptic link to the mesoaccumbens DA neurons that modulate approach behaviors.

Acetylcholine↗

PubMed2006

Chronic stress increases the plasmalemmal distribution of the norepinephrine transporter and the coexpression of tyrosine hydroxylase in norepinephrine axons in the prefrontal cortex.

Norepinephrine (NE) potently modulates the cognitive and affective functions of the prefrontal cortex (PFC). Deficits in NE transmission are implicated in psychiatric disorders, and antidepressant drugs that block the NE transporter (NET) effectively treat these conditions. Our initial ultrastructural studies of the rat PFC revealed that most NE axons (85-90%) express NET primarily within the cytoplasm and lack detectable levels of the synthetic enzyme tyrosine hydroxylase (TH). In contrast, the remaining 10-15% of PFC NE axons exhibit predominantly plasmalemmal NET and evident TH immunoreactivity. These unusual characteristics suggest that most PFC NE axons have an unrecognized, latent capacity to enhance the synthesis and recovery of transmitter. In the present study, we used dual-labeling immunocytochemistry and electron microscopy to examine whether chronic cold stress, a paradigm that persistently increases NE activity, would trigger cellular changes consistent with this hypothesis. After chronic stress, neither the number of profiles exhibiting NET labeling nor their size was changed. However, the proportion of plasmalemmal NET nearly doubled from 29% in control animals to 51% in stressed rats. Moreover, the expression of detectable TH in NET-labeled axons increased from only 13% of profiles in control rats to 32% of profiles in stressed animals. Despite the consistency of these findings, the magnitude of the changes varied across individual rats. These data represent the first demonstration of activity-dependent trafficking of NET and expression of TH under physiological conditions and have important implications for understanding the pathophysiology and treatment of stress-related affective disorders.

Animals↗

PubMed2006

Selective elimination of glutamatergic synapses on striatopallidal neurons in Parkinson disease models.

Parkinson disease is a common neurodegenerative disorder that leads to difficulty in effectively translating thought into action. Although it is known that dopaminergic neurons that innervate the striatum die in Parkinson disease, it is not clear how this loss leads to symptoms. Recent work has implicated striatopallidal medium spiny neurons (MSNs) in this process, but how and precisely why these neurons change is not clear. Using multiphoton imaging, we show that dopamine depletion leads to a rapid and profound loss of spines and glutamatergic synapses on striatopallidal MSNs but not on neighboring striatonigral MSNs. This loss of connectivity is triggered by a new mechanism-dysregulation of intraspine Cav1.3 L-type Ca(2+) channels. The disconnection of striatopallidal neurons from motor command structures is likely to be a key step in the emergence of pathological activity that is responsible for symptoms in Parkinson disease.

Animals↗

PubMed2005

Mediodorsal thalamic afferents to layer III of the rat prefrontal cortex: synaptic relationships to subclasses of interneurons.

The mediodorsal nucleus of the thalamus (MD) represents the main subcortical structure that projects to the prefrontal cortex (PFC) and it regulates key aspects of the cognitive functions of this region. Within the PFC, GABA local circuit neurons shape the activity patterns and hence the "memory fields" of pyramidal cells. Although the connections between the MD and PFC are well established, the ultrastructural relationships between projecting fibers from the MD and different subclasses of GABA cells in the PFC are not known. In order to address this issue in the rat, we examined MD axons labeled by tract-tracing in combination with immunogold-silver to identify different calcium-binding proteins localized within separate populations of interneurons. Electron micrographic examination of PFC sections from these animals revealed that MD terminals made primarily asymmetric synapses onto dendritic spines and less commonly onto dendritic shafts. Most of the dendrites receiving MD synaptic input were immunoreactive for parvalbumin (ParV), whereas MD synapses onto dendrites labeled for calretinin or calbindin were less frequent. We also observed that some MD terminals were themselves immunoreactive for calcium-binding proteins, again more commonly for ParV. These results suggest that the MD exerts a dual influence on PFC pyramidal cells: direct inputs onto spines and an indirect influence mediated via synapses onto each subclass of interneurons. The apparent preferential input to ParV cells endows MD afferents with a strong indirect inhibitory influence on pyramidal neuron activity by virtue of ParV cell synapses onto soma, proximal dendrites, and axon initial segments.

Afferent Pathways↗

PubMed2005

Laterodorsal tegmental projections to identified cell populations in the rat ventral tegmental area.

Projections from the laterodorsal tegmentum (LDT) to the ventral tegmental area (VTA) contribute to the activity of dopamine (DA) and GABA cells and, hence, to the affective and cognitive functions of this region. LDT afferents arise from neurochemically diverse cell types and mediate multiple functional influences. However, the VTA cell populations that receive LDT afferents are unknown and were investigated here by anterograde and retrograde tract-tracing in combination with immunocytochemistry to distinguish DA and GABA cells. Approximately 50% of the LDT to VTA pathway formed asymmetric, presumably excitatory synapses that innervated DA and GABA cells in rough proportion to their representation within the VTA. This portion of the LDT innervation appeared to selectively target DA but not GABA mesoaccumbens neurons and provide a relatively nonselective input to both DA and GABA mesoprefrontal cells. The remaining LDT axons formed symmetric, presumably inhibitory synapses with a different pattern of cellular targets that included a preferential input to GABA neurons of both mesoaccumbens and mesoprefrontal populations and an apparently selective innervation of mesoprefrontal and not mesoaccumbens DA neurons. These data suggest that the LDT mediates a convergent excitatory and inhibitory influence on both mesoprefrontal DA and GABA cells but a divergent impact on mesoaccumbens neurons that is likely to excite DA cells and inhibit GABA neurons. Combined with our previous description of prefrontal cortical afferents, our data also indicate that mesoaccumbens DA neurons receive putative excitatory drive from the LDT, whereas mesoprefrontal DA cells receive convergent excitation from both cortical and brainstem sources.

Acetylcholine↗

PubMed2004

Ultrastructure at carbon fiber microelectrode implantation sites after acute voltammetric measurements in the striatum of anesthetized rats.

This work seeks to establish the feasibility of characterizing the ultrastructure of brain tissue disruption associated with the implantation of carbon fiber voltammetric microelectrodes. In vivo recording was performed by fast scan cyclic voltammetry in conjunction with carbon fiber microelectrodes (3.5 microm radius) in the striatum of rats anesthetized with chloral hydrate. After 4 h of in vivo recording, the microelectrodes were removed from the brain and the animals underwent intracardial perfusion. Brain tissue was collected and sectioned in the horizontal plane perpendicular to the axis of the microelectrodes. With microelectrodes of a conventional single barreled design, the tissue tracks were often too small to be followed by light microscopy to the point of deepest penetration, which would correspond to the implantation site of the carbon fiber itself. The enlarged tissue tracks formed by the implantation of double barreled electrodes, however, could be followed to their termination by light microscopy. Anatomical mapping was used to identify the fields laying 100 microm deeper than the deepest trace of such tracks. Electron microscopy of these fields revealed a spot of tissue damage presumed to be associated with the implantation site of the carbon fiber microelectrode. The spot of maximal tissue damage had a radius of 2.5 microm and was surrounded by an annular region with a width of 4 microm that contained a mix of healthy and damaged elements. Beyond this annular region, i.e. beyond 6.5 microm from the center of the spot of maximal damage, signs of microelectrode-associated damage were rare and consisted primarily of neurons with darkened cytoplasm.

Animals↗

PubMed2004

Ultrastructural interactions between terminals expressing the norepinephrine transporter and dopamine neurons in the rat and monkey ventral tegmental area.

The norepinephrine (NE) system is implicated in the etiology and treatment of depression and drugs blocking the NE transporter (NET) are effective antidepressants. It is possible that dopamine (DA) also plays a role in depression and the action of antidepressant drugs, although the mechanisms whereby NE and DA interact have not been fully elaborated. We examined whether NE neurons might alter DA transmission via synaptic projections to cells in the ventral tegmental area (VTA) by using electron microscopic dual labeling immunocytochemistry in the rat and monkey. NET was used as a marker for NE axons, whereas the catecholamine synthetic enzyme, tyrosine hydroxylase (TH), served as a label for DA neurons. We observed three types of spatial relationships between these profiles that were similar in type but varied in frequency between rodent and primate. The most common arrangement involved nonsynaptic appositions between NET-immunoreactive (-ir) axons and TH-ir dendrites. Such relationships may facilitate extrasynaptic actions of NE on DA cell activity. The other commonly observed arrangement involved adjacent profiles that were otherwise separated by glia. These relationships may represent regions where NE is prevented from reaching DA cells. In only a few cases were synapses observed between NET-ir axons and TH-ir dendrites. This finding suggests that NE can synaptically regulate DA neurons, although functional interactions are more likely to involve extrasynaptic mechanisms. Finally, in the VTA of both species the majority of NET-ir axons exhibited no detectable TH immunoreactivity. The latter finding agrees with observations in cortical regions and represents the first report of its type in a subcortical structure.

Animals↗

PubMed2004

Prefrontal cortical projections to the rat dorsal raphe nucleus: ultrastructural features and associations with serotonin and gamma-aminobutyric acid neurons.

Studies of human brain indicate that both the ventromedial prefrontal cortex (PFC) and the dorsal raphe nucleus (DRN) may be dysfunctional in major depressive illness, making it important to understand the functional interactions between these brain regions. Anatomical studies have shown that the PFC projects to the DRN, although the synaptic targets of this excitatory pathway have not yet been identified. Electrophysiological investigations in the rat DRN report that most serotonin neurons are inhibited by electrical stimulation of the PFC, suggesting that this pathway is more likely to synapse onto neighboring gamma-aminobutyric acid (GABA) neurons than onto serotonin cells. We tested this hypothesis by electron microscopic examination of DRN sections dually labeled for biotin dextran amine anterogradely transported from the PFC and immunogold-silver labeling for tryptophan hydroxylase (TrH) or for GABA. In the DRN, the majority of PFC axons either synapsed onto unlabeled dendrites or failed to form detectable synapses in single sections. Other PFC axons synapsed onto either TrH- or GABA-immunolabeled processes. Considerably more tissue sampling was necessary to detect PFC synapses onto TrH- than onto GABA-labeled dendrites, suggesting that the latter connections are more common. In other cases, PFC terminals and TrH- or GABA-immunoreactive dendrites either were closely apposed, without forming detectable synapses, or were separated by glial processes. These results provide potential anatomical substrates whereby the PFC can both directly and indirectly regulate the activity of serotonin neurons in the DRN and possibly contribute to the pathophysiology of depression.

Animals↗

PubMed2003

Ultrastructural localization of the norepinephrine transporter in superficial and deep layers of the rat prelimbic prefrontal cortex and its spatial relationship to probable dopamine terminals.

The prefrontal cortex (PFC) is a likely site of action for the therapeutic efficacy of antidepressants that inhibit norepinephrine (NE) reuptake. Moreover, drugs that block the NE transporter (NET) increase extracellular levels of both NE and dopamine (DA), an interaction that may contribute to their therapeutic properties. To examine the subcellular localization of NET and to investigate the spatial relationships between presumed NE and DA axons within the rat prelimbic PFC, we combined immunogold-silver localization of NET with immunoperoxidase staining for the catecholamine synthetic enzyme tyrosine hydroxylase (TH). An additional aim was to quantify the proportion of profiles dually labeled for NET and TH to test the common observation that TH immunolabeling is relatively selective for DA axons. NET-immunoreactive (NET-ir) axonal profiles were typically unmyelinated and occasionally were observed to form symmetric axodendritic synapses. The majority of immunogold NET labeling was unexpectedly observed in the cytoplasm rather than on the plasma membrane. Furthermore, in tissue dually labeled for both NET and TH, only 8-10% of profiles contained both markers. Unlike observations for singly labeled profiles, gold-silver particles for NET in dually labeled axons were localized primarily to the plasmalemma. A systematic survey of terminals labeled only for TH revealed that they were typically separated by at least 1.2 mum from NET-ir varicosities, and the two profile types were not seen to contact common targets. These results suggest that, in the rat PFC, NE axons (1) contain predominantly cytoplasmic NET, (2) infrequently contain TH immunolabeling, and (3) may interact with probable DA afferents by means of extrasynaptic mechanisms.

Animals↗

PubMed2003

Projections from the paraventricular nucleus of the thalamus to the rat prefrontal cortex and nucleus accumbens shell: ultrastructural characteristics and spatial relationships with dopamine afferents.

The paraventricular nucleus of the thalamus (PVT) participates in the functional integration of limbic cortical and striatal circuitry. In the rat, the PVT projects to the deep layers of the medial prefrontal cortex (PFC) and to the shell of the nucleus accumbens (NAc). However, the synaptic organization of PVT afferents within these regions remains undescribed. Furthermore, although dopamine (DA) modulates excitatory glutamate transmission in both areas, possible anatomic substrates for specific DA modulation of PVT inputs have not yet been investigated. To address these issues, immunoperoxidase labeling for tyrosine hydroxylase (TH) in DA axons was combined with anterograde tract-tracing, either by biotinylated dextran amine (BDA) labeled with immunogold-silver or by degeneration after lesions of the PVT. In both regions, and with either tracing method, PVT terminals formed primarily asymmetric axospinous synapses; in the NAc, a proportion of PVT terminals also synapsed onto dendrites. PVT profiles in both regions were often seen in direct apposition to TH-immunoreactive axons; this association was more evident in the NAc where the DA innervation is denser. Within the PFC, PVT profiles and TH-labeled axons were occasionally apposed to the same dendrites, but synaptic specializations were not typically seen at these seeming points of convergence. Within the NAc, PVT profiles occasionally made synapses onto spines and distal dendrites that received convergent synapses from TH-immunoreactive varicosities. These findings represent the first demonstration of postsynaptic convergence between DA and thalamic afferents to a striatal region and are consistent with direct synaptic modulation of PVT transmission by DA in the NAc but not the PFC.

Afferent Pathways↗

PubMed2003

Anatomical substrates for glutamate-dopamine interactions: evidence for specificity of connections and extrasynaptic actions.

For normal regulation of motor, affective, and cognitive functions, dopamine provides an essential modulation of glutamate transmission within multiple brain regions. This paper will review three principal anatomical substrates for such interactions. First, dopamine modulates the activity of glutamate neurons within the cerebral cortex. Evidence will be reviewed for dopamine regulation of pyramidal neurons in the prefrontal cortex via synaptic and extrasynaptic mechanisms and through indirect effects mediated by GABA cells. Second, glutamate neurons innervate dopamine cells within the ventral tegmental area. Evidence will be described for selective glutamate input from the prefrontal cortex or the brain stem tegmentum to different populations of dopamine cells. The third level of interaction occurs within target regions via convergent synaptic or extrasynaptic regulation of common neurons. Such convergence will be reviewed for the basal ganglia, prefrontal cortex, and amygdala. Together, these substrates for glutamate-dopamine interactions provide several mechanisms for normal regulation of brain function. Sites of modulatory interaction between dopamine and glutamate also suggest circuit alterations that might contribute to the pathophysiology of mental health disorders and provide potential sites for therapeutic intervention in these conditions.

Amygdala↗

PubMed2002

Selective prefrontal cortex inputs to dopamine cells: implications for schizophrenia.

Dopamine (DA) neurons in the substantia nigra (SN) and ventral tegmental area (VTA) form several projection systems with diverse functions, such as motor planning through the striatum, reward seeking via the nucleus accumbens (NAc), and cognitive control through the prefrontal cortex (PFC). Disruptions in DA cell activity profoundly impair these functions and contribute to serious clinical conditions such as Parkinson's disease and schizophrenia. DA neurons have been extensively investigated in studies detailing their anatomy, physiology, and neurochemical regulation. Moreoever, recordings from behaving animals suggest that phasic changes in DA cell firing signal expectancy or attentional shifts associated with approach/avoidance behavior. These ideas raise interesting questions regarding how DA neurons are regulated to produce such phasic signals. For example, it is not yet known how different classes of DA projection neurons are regulated by specific inputs. In the first study of its kind within the VTA, our laboratory recently demonstrated that excitatory inputs from the PFC synapse selectively onto DA neurons that project back to the PFC but not onto DA cells that project to the NAc. These findings may explain some of the unique functional properties of mesoprefrontal DA neurons. Moreover, the results are important for understanding the pathophysiology of mental disorders such as schizophrenia.

Cognition↗