Biology subjects

Isaac, J.

Publications and source records attributed to Isaac, J..

10 recordsLinked to original sources

bioRxiv2026

Projection populations form a dorsoventral gradient of reward representations in the lateral septum

Several decades ago, the septal region was identified as the most dependable location of intracranial self-stimulation (ICSS) in the brain, but the neural substrates that mediate septal self-stimulation are still unknown. One part of the septal region, the lateral septum (LS), contributes to a number of motivated behaviors and may promote reward-seeking. However, the LS contains different anatomical subregions, complicating the characterization of its reward representations. We examine the responses of LS neurons along its dorsoventral axis using cellular resolution calcium imaging during an operant assay. We find that a greater proportion of neurons are excited in response to sucrose reward in the dorsal LS, while a greater proportion are inhibited in response to sucrose reward in the ventral LS. Additionally, we identify two distinct LS projection populations, one to the nucleus accumbens (NAc) and another to the bed nucleus of the stria terminalis (BNST), which are located in the dorsal and ventral regions of the LS, respectively. These two projection populations also have opposing reward responses and their corresponding optogenetic manipulation supports ICSS. These findings demonstrate how LS projection populations contribute to its functional heterogeneity, especially as it pertains to reward-seeking behavior.

neuroscience↗

bioRxiv2025

Non-overlapping social and food reward representations in the basolateral amygdala

The ability to consider and appraise positively valenced stimuli in the environment, such as food and social interaction, to guide appropriate action is important for survival of most animals. Several studies have compared how food and social rewards are represented in different regions involved in reward processing and found either overlapping or distinct representations. In the basolateral amygdala (BLA) there seems to be opposing evidence for both shared and unique encoding of social and nonsocial stimuli. In our recent work, we found that the medial prefrontal cortex (mPFC), a region reciprocally connected to the BLA, has distinct social and food representations using a novel self-paced two-choice assay. Given the BLA and mPFCs differing roles in reward processing, it is important to understand how these two nodes may differ in their encoding reward types within the same assay. To resolve how the BLA encodes social and food information, we recorded the activity of individual BLA neurons in female and male mice during a two-choice social-sucrose operant task. We found that BLA neurons robustly and distinctly respond to social and food reward. In contrast to the mPFC, BLA neurons did not show a bias towards social reward responsiveness and instead showed equal social/sucrose representation, in males, or a sucrose reward bias, in females. BLA neurons were sensitive to internal state - water deprivation increased the proportion of sucrose reward responsive neurons. Additionally, sucrose reward responsive BLA neurons were differentially sensitive to reward omissions, such that neurons that were excited by sucrose reward were more sensitive to reward omissions compared to those inhibited by reward. Together, these findings demonstrate distinct, heterogeneous response profiles within the BLA to social and food rewards, in a manner different from the mPFC.

neuroscience↗

bioRxiv2025

An amygdalopontine pathway promotes motor programs of ingestion

Despite internal cues that signal fullness, animals can continue eating when motivated by context or palatability. The neural pathways and signals that enable animals to override these fullness cues remain unclear. We examined a central amygdala (CeA) projection to the dorsolateral pons that targets the parabrachial nucleus, a well-established meal termination center, and the adjacent supratrigeminal nucleus, a region that controls orofacial movements. Activity in this CeApons pathway correlated with the animals licking behavior but was not modulated by metabolic need or palatability cues. CeApons stimulation caused animals to overeat, consume non-edible objects within reach, or exhibit ingestion-like behaviors--licking, chewing, and grasping--even when no target was present. Depending on training and context, stimulation elicited either licking or pellet consumption, suggesting that CeApons promotes a flexible, goal-directed ingestive state by recruiting consummatory motor circuits rather than simply suppressing satiety signals. These findings highlight how forebrain-brainstem interactions can re-engage feeding behavior beyond homeostatic need.

neuroscience↗

bioRxiv2025

Germline-targeting HIV Envelope SOSIP immunization more frequently elicits broadly-neutralizing antibody precursor responses in infant compared to juvenile rhesus macaques

A vaccine capable of inducing broadly neutralizing antibodies (bnAbs) is essential for effective prevention against HIV in children and adolescents. Germline-targeting vaccine strategies aim to stimulate bnAb precursor B cells through carefully designed immunogens, such as the stabilized SOSIP trimers, which mimic native HIV envelope (Env) proteins while presenting key neutralizing epitopes to germline B cell receptors. Given the ability of children living with HIV to develop bnAbs earlier and at a higher frequency than adults, we compared the immunogenicity of a CD4 binding site (CD4bs) bnAb germline-targeting SOSIP trimer immunization strategy in infant (n = 5) and juvenile (n = 4) rhesus macaques (RMs). Animals received 3 doses of the germline-targeting BG505 GT1.1 immunogen, followed by 3 boosts of wild-type BG505 SOSIP, each adjuvanted with the TLR7/8 agonist, 3M-052-SE. After 1.5 years, the RMs were further boosted with a mixed clade B Env trimer nanoparticle to enhance heterologous virus neutralization responses. This germline-targeting strategy induced equivalent titers of neutralizing antibodies in both groups of RMs, yet the infants exhibited a higher magnitude of vaccine-specific IgG binding. Notably, after 3 doses of BG505 GT1.1 SOSIP, infants had higher BG505 GT1.1-specific IgD- B cells. Upon completion of the vaccine regimen, 4 of 5 infants developed a CD4bs bnAb precursor response detectable in serum compared to only 1 of 4 juveniles. Finally, administration of the mixed clade B nanoparticle was able to increase the breadth of antibody responses in 3 of 5 infants and 2 of 4 juveniles. These results suggest that immunization in early-life may enhance bnAb induction and highlight the potential for future pediatric HIV-1 vaccine strategies. Author SummaryVaccines that can generate antibody responses that have breadth and potency in neutralization can protect children and adolescents from acquiring multi-strain viruses like HIV. Increasingly, vaccine strategies have become better tailored to elicit these broadly neutralizing antibodies (bnAbs), such as the germline-targeting HIV envelope antigens, which have shown great promise. To determine if we could elicit protective antibody responses against HIV in early life, we immunized infant and juvenile monkeys using the same vaccine strategy. In this study, we found that while both infants and juveniles developed similar levels of antibodies that could neutralize HIV, the infants showed stronger antibody responses in several key areas. Moreso, infants developed the type of early antibody response that researchers believe is needed to eventually evolve into broadly neutralizing antibodies. These findings suggest that initiating HIV vaccination earlier in life may offer a better chance at generating the bnAbs needed to protect against various HIV strains. Our work highlights the potential benefits of initiating an HIV vaccine regimen in childhood.

immunology↗

bioRxiv2025

Organization of brainwide inputs to discrete lateral septum projection populations

The lateral septum (LS) is anatomically positioned to play a critical role in directing information from the hippocampus and cortex to downstream subcortical structures, such as the hypothalamus. In fact, early anatomical tracing studies investigated the organization of hippocampal inputs to the LS and its hypothalamic outputs to begin to understand how its structure might relate to its function. These studies also characterized the cellular anatomy of the LS and the organization of different molecular markers within it. However, relatively little is known about the organization of other, non-hypothalamic projection populations within the LS and what types of input these different projection populations receive. Here, we used retrograde tracing to determine the organization of LS projections to six different brain regions that mediate various social behaviors. We found that these projection populations occupy discrete anatomical compartments within the LS. We then used a monosynaptic rabies tracing strategy to map brainwide inputs to these six discrete LS projection populations and examine how different brain regions innervate them. We identified unique region-dependent patterns of inputs to individual LS projection populations. In particular, we observed differences in cortical, hippocampal and thalamic innervation of the six different LS projection populations, while the hypothalamic inputs were largely similar across projection populations. Thus, this study provides insight into the anatomical connectivity that may underlie the functional heterogeneity of the LS.

neuroscience↗

bioRxiv2024

A ventral hippocampal-lateral septum pathway regulates social novelty preference.

The ability to distinguish strangers from familiar individuals is crucial for the survival of most mammalian species. In humans, an inability to recognize kin and familiar individuals and engage in appropriate behaviors is associated with several types of dementia, including Alzheimers disease. Mice preferentially spend more time investigating a novel individual relative to a familiar individual. Yet, how social novelty related information drives increased investigation of the novel animal remains poorly understood. Recent evidence has implicated the ventral hippocampus (vHPC) as a key node in encoding information about conspecific identity. Of particular interest are vHPC projections to the lateral septum (LS), a region that has been implicated in driving a wide range of motivated social behaviors. In this study using chemogenetics, optogenetics and monosynaptic rabies tracing, we identified a novel vHPC-LS-ventral tegmental area (VTA) pathway that is necessary for mice to preferentially investigate novel conspecifics. Using monosynaptic rabies tracing, we established that LS neurons make direct monosynaptic connections onto dopaminergic neurons in the VTA. Thus, we have identified a potential pathway via which conspecific identity could be transformed to drive motivated social behaviors.

neuroscience↗

bioRxiv2023

Germline-targeting SOSIP trimer immunization elicits precursor CD4 binding-site targeting broadly neutralizing antibodies in infant macaques.

A vaccine that can achieve protective immunity prior to sexual debut is critical to prevent the estimated 410,000 new HIV infections that occur yearly in adolescents. As children living with HIV can make broadly neutralizing antibody (bnAb) responses in plasma at a faster rate than adults, early childhood is an opportune window for implementation of a multi-dose HIV immunization strategy to elicit protective immunity prior to adolescence. Therefore, the goal of our study was to assess the ability of a B cell lineage-designed HIV envelope SOSIP to induce bnAbs in early life. Infant rhesus macaques (RMs) received either BG505 SOSIP or the germline-targeting BG505 GT1.1 SOSIP (n=5/group) with the 3M-052-SE adjuvant at 0, 6, and 12 weeks of age. All infant RMs were then boosted with the BG505 SOSIP at weeks 26, 52 and 78, mimicking a pediatric immunization schedule of multiple vaccine boosts within the first two years of life. Both immunization strategies induced durable, high magnitude binding antibodies and plasma autologous virus neutralization that primarily targeted the CD4-binding site (CD4bs) or C3/465 epitope. Notably, three BG505 GT1.1-immunized infants exhibited a plasma HIV neutralization signature reflective of VRC01-like CD4bs bnAb precursor development and heterologous virus neutralization. Finally, infant RMs developed precursor bnAb responses at a similar frequency to that of adult RMs receiving a similar immunization strategy. Thus, a multi-dose immunization regimen with bnAb lineage designed SOSIPs is a promising strategy for inducing protective HIV bnAb responses in childhood prior to adolescence when sexual HIV exposure risk begins.

immunology↗

bioRxiv2023

Sex differences in neural representations of social and nonsocial reward in the medial prefrontal cortex.

The reinforcing nature of social interactions is necessary for the maintenance of appropriate social behavior. However, the neural substrates underlying social reward processing and how they might differ based on the sex and internal state of the animal remains unknown. It is also unclear whether these neural substrates are shared with those involved in nonsocial rewarding processing. We developed a fully automated, novel two choice (social-sucrose) operant assay in which mice choose between social and nonsocial rewards to directly compare the reward-related behaviors associated with two competing stimuli. We performed cellular resolution calcium imaging of medial prefrontal cortex (mPFC) neurons in male and female mice across varying states of water restriction and social isolation. We found that mPFC neurons maintain largely non-overlapping, flexible representations of social and nonsocial reward that vary with internal state in a sex-dependent manner. Additionally, optogenetic manipulation of mPFC activity during the reward period of the assay disrupted reward-seeking behavior across male and female mice. Thus, using a novel operant assay, we have identified sex-dependent, non-overlapping neural representations of social and nonsocial reward in the mPFC that vary with internal state and that are essential for appropriate reward-seeking behavior.

neuroscience↗

bioRxiv2023

Transient cAMP production drives rapid and sustained spiking in brainstem parabrachial neurons tosuppress feeding

Brief stimuli can trigger longer lasting brain states. G protein-coupled receptors (GPCRs) could help sustain such states by coupling slow-timescale molecular signals to neuronal excitability. Brainstem parabrachial nucleus glutamatergic neurons (PBNGlut) regulate sustained brain states such as pain, and express Gs-coupled GPCRs that increase cAMP signaling. We asked whether cAMP directly influences PBNGlut excitability and behavior. Both brief tail shocks and brief optogenetic stimulation of cAMP production in PBNGlut neurons drove minutes-long suppression of feeding. This suppression matched the duration of prolonged elevations in cAMP, Protein Kinase A (PKA), and calcium activity in vivo and in vitro. Shortening this elevation in cAMP reduced the duration of feeding suppression following tail shocks. cAMP elevations in PBNGlut neurons rapidly lead to sustained increases in action potential firing via PKA-dependent mechanisms. Thus, molecular signaling in PBNGlut neurons helps prolong neural activity and behavioral states evoked by brief, salient bodily stimuli.

neuroscience↗

bioRxiv2018

Cellular and Synaptic Phenotype Compensations Limit Circuit Disruption in Fmr1-KO Mouse Layer 4 Barrel Cortex but Fail to Prevent Deficits in Information Processing

Sensory hypersensitivity is a common and debilitating feature of neurodevelopmental disorders such as Fragile X Syndrome (FXS). However, how developmental changes in neuronal function ultimately culminate in the network dysfunction that underlies sensory hypersensitivities is not known. To address this, we studied the layer 4 barrel cortex circuit in Fmr1 knockout mice, a critical sensory processing circuit in this mouse model of FXS. By systematically studying cellular and synaptic properties of layer 4 neurons and combining with cellular and network simulations, we explored how the array of phenotypes in Fmr1 knockout produce circuit pathology during development that result in sensory processing dysfunction. We show that many of the cellular and synaptic pathologies in Fmr1 knockout mice are antagonistic, mitigating circuit dysfunction, and hence can be regarded as compensatory to the primary pathology. Despite this compensation, the layer 4 network in the Fmr1 knockout exhibits significant alterations in spike output in response to ascending thalamocortical input that we show results in impaired sensory encoding. We suggest that it is this developmental loss of layer 4 sensory encoding precision that drives subsequent developmental alterations in layer 4 - layer 2/3 connectivity and plasticity observed in the Fmr1 knockout, and is a critical process producing sensory hypersensitivity.

neuroscience↗